Xanthomonas axonopodis pv. manihotis (Xam) seriously affects cassava yield. Genes encoding nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domains are among the most important disease resistance genes in plants that are specifically involved in the response to diverse pathogens. However, the in vivo roles of NBS-LRR remain unclear in cassava (Manihot esculenta). In this study, we isolated four MeLRR genes and assessed their expression under salicylic acid (SA) treatment and Xam inoculation. Four MeLRR genes positively regulate cassava disease general resistance against Xam via virus-induced gene silencing (VIGS) and transient overexpression. During cassava-Xam interaction, MeLRRs positively regulated endogenous SA and reactive oxygen species (ROS) accumulation and pathogenesis-related gene 1 (PR1) transcripts. Additionally, we revealed that MeLRRs positively regulated disease resistance in Arabidopsis. These pathogenic microorganisms include Pseudomonas syringae pv. tomato, Alternaria brassicicola, and Botrytis cinerea. Our findings shed light on the molecular mechanism underlying the regulation of cassava resistance against Xam inoculation.Cassava bacterial blight (CBB) caused by  R genes) usually act as receptors of pathogen-encoded effector proteins, which are often secreted by pathogens directly into host cells  of NBS-LRR proteins usually contain the Toll/interleukin-1 receptor-like (TIR) domain, coiled-coil (CC) domain, or resistance to powdery mildew 8 (RPW8) domain, and the carboxyl terminus (C-terminus) contain a zinc-finger transcription factor-related domain containing the WRKY sequence (WRKY domain) , CC-NBS-LRR (CNL), and RPW8-NBS-LRR (RNL) proteins (Disease resistance genes (st cells . R genesomycetes . In the  species . Among tn plants . The ami domain) . Based oproteins .NBS-LRR-coding genes  genome  (Manihot esculenta) (Sorghum bicolor) (Triticum aestivum) (Gossypium hirsutum) (Zea mays) (Glycine max) (Vitis vinifera) (Dioscorea rotundata) (PR) genes (NB-ARC domain-containing (GbaNA1) gene impaired cotton resistance to Verticillium dahliae Vd991  genome , constit) genome . In the  indica) , cassavaculenta) , sorghumbicolor) , wheat (estivum) , cotton irsutum) , maize (ea mays) , soybeanine max) , grapeviinifera) , and yamtundata) . In recetundata) . ActivatR) genes . In cottae Vd991 . Similaraffected . NBS-LRRaffected . Yoodee  cassava , their rX. axonopodis pv. manihotis = X. phaseoli pv. manihotis)  and anthracnose disease (Colletotrichum gloeosporioides)  , cassavarioides) . Therefo viruses . A clustelection . HoweverNBS-LRR genes that showed high transcription level after pathogen infection attracted our attention. The expression levels of four chosen MeLRRs were significantly induced by exogenous application of SA treatment and Xam inoculation. Moreover, these genes positively regulated cassava resistance to Xam inoculation. The functional analysis of MeLRR genes will offer potential roles in genetic breeding for disease-resistant cassava.In this study, we analyzed the published transcriptome databases of cassava-pathogens interaction . Within NBS-LRRs in cassava, including both TIR-NBS-LRR and CC-NBS-LRR. Their transcript levels were analyzed through RNA-seq in response to CBSV and C. gloeosporioides infection  were both induced under CBSV and C. gloeosporioides infection and selected for further analysis. The four MeLRR proteins have typical leucine-rich repeats, which are named MeLRR1 (Manes. 11G053000.1), MeLRR2 (Manes. 03G071700.1), MeLRR3 (Manes. 13G036800.1), and MeLRR4 (Manes. 07G107800.1), located on chromosomes 11, 3, 13, and 7, respectively. MeLRR1, MeLRR3, and MeLRR4 belong to CC-NBS-LRR protein, while MeLRR2 is one of the TIR-NBS-LRR protein. Bioinformatics predicted that the MeLRR proteins were unstable and hydrophilic  leaves were infected with 35S:GFP or 35S:GFP-MeLRR1,−2,−3,−4 plasmid as described by 35S:GFP  of MeLRRs were cloned and inserted into the poly-cloning sites of the fusion expression vector pEGAD and fused upstream to a green florescence protein (GFP) fusion partner by the constitutive  35S:GFP .MeLRRs in response to SA treatment and Xam inoculation were analyzed by qRT-PCR . Under SA treatment, the expressions of MeLRR1, MeLRR3, and MeLRR4 were induced and peaked at 1 h post treatment (hpt), while MeLRR2 showed the highest level at 3 hpt . The partial sequences of MeLRR1 (453 bp), MeLRR2 (441 bp), MeLRR3 (433 bp) and MeLRR4 (423 bp) were individually inserted into pTRV2 plasmid to construct VIGS vector. At 14 days post-infection (dpi) in cassava infected with Agrobacterium GV3101 carrying the pTRV-MeLRR plasmids, qRT-PCR was performed to detect the target gene transcript level. The transcript level of the target MeLRR-1,-2,-3,-4 genes were significantly decreased in the MeLRR-silenced cassava leaves compared to the pTRV empty vector. The silencing efficiency of MeLRR-1,-2,-3,-4 was 46.33 (± 2.31)%, 15.28 (± 0.49)%, 30.22 (± 2.28)%, and 17.45 (± 0.87)% , respectively  in one VIGS line, the transcript levels of all four target genes were significantly decreased  gene and B. cinerea BcActA (XM_024697950.1) gene  gene  with theectively .AtICS1, AtPDF1.2, AtPR1, AtPR2, AtPR5, and AtTGA3 in WT and MeLRR overexpression lines upon A. brassicicola, B. cinerea, and P. syringae pv. tomato DC3000 infection , and its production in plants represents the successful recognition of pathogen infection and pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) . In casse to CBB . TherefoXam regulate plant immune  effectors and type III effectors (T3Es) of t immune . Such asune , variety South China 124 (SC124), and N. benthamiana were cultivated in mixed soil  in a greenhouse with 16/8 h light/dark at 28/22°C, 60–70% relative humidity with irradiance of 130–150 uE.m–2.s–1. A. thaliana ecotype Col-0 (Columbia-0) seedlings were cultivated in the mixed soil under fluorescent light (130–150 uE.m–2.s–1) and were grown under 16/8 h light/dark at 22°C. For axenic growth, N. benthamiana, and A. thaliana seeds were sterilized  and sown on half-strength MS (Murashige and Skoog) medium  with 0.4% agar powder and 2% (w/v) sucrose. The seeds were grown in chambers under 16/8 h light/dark at 22°C and 130–150 uE.m–2.s–1. For expression analysis, 4-week-old cutting seedlings of cassava leaves were sprayed with 5 mmol/L salicylic acid or Xam suspension for 0, 1, 3, 6, 12, or 24 h, and the bacterial solution was diluted to 4 × 108 colony-forming units/mL (cfu/mL) using 10 mmol/L MgCl2 with 0.05% Silwet L-77.Cassava  , Durio zibethinus (XP_022746274.1), H. brasiliensis , J. curcas , Populus alba , P. euphratica (XP_011001622.1), P. trichocarpa (RQO87881.1), Ricinus communis (EEF44774.1), Theobroma cacao (XP_01796 9995.1), Vernicia montana (AMM43068.1), V. vinifera (XP_010657.1), and Ziziphus jujuba (XP_024924720.1), respectively.The sequences of me v131) . The Proty index . Alignmety index . The 24 Arabidopsis and cassava gene transcripts were normalized to the AtAct2 gene (AT3G18780) and elongation factor 1α  using the comparative 2–ΔΔCt method, respectively  of A. brassicicola were designed by Primer3Plus3 to find optimal primers . cDNA synthesis was performed using the Tiangen FastQuant RT kit  with 20-μl reaction mixture. qRT-PCR analysis was performed using UltraSYBR Mixture (low ROX)  in an ABI QuantStudio™ 6 flex Real-Time PCR System . The PCR cycling conditions were 95°C for 10 min, followed by 40 cycles at 95°C for 15 s and 60°C for 1 min. The ectively . The qRT primers , and theMeLRR1,-2,-3,-4 were amplified and cloned into the pEGAD vector (Promoter CaMV35S:GFP) via appropriate restriction enzyme digestion and T4 DNA ligase. The recombinant plasmids and empty vector were transformed into Agrobacterium GV3101. Then, the A. tumefaciens suspension was used to infect the leaves of cassava or tobacco as described by 8 cfu/mL of pathogenic bacteria Xam used for disease resistance assay, include number of Xam populations, MePR1 transcript level, and symptoms of cassava bacterial blight at 0 and 1 dpi, respectively.For overexpression, the full-length coding regions of MeLRRs and the online siDirect 2.04 tools  for 24 h at room temperature (The cassava or perature . The leaperature .P. syringae pv. tomato (Pst) DC3000 was streaked on LB medium with 50 mg/L of rifampicin at 28°C and shaken to OD600 reached 0.6. Thereafter, a fresh bacterial culture of Pst DC3000 was diluted to 4 × 108 cfu/mL in 10 mmol/L MgCl2 and 0.05% Silwet L-77 and then sprayed on 24-day-old Arabidopsis leaves. The A. brassicicola and B. cinerea strains were cultured on potato dextrose agar (PDA) medium with 2% (w/v) sucrose at 28°C. Conidia were suspended in distilled water for plant infection. Spore suspensions (about 4 × 106 spores/mL) of A. brassicicola and B. cinerea were sprayed on Arabidopsis leaves. The infected plants were grown in an incubator at 90% RH and 22°C. At 0, 2, and 4 dpi, the number of Pst DC3000 bacteria was determined, as well as the fungal actin gene transcript in leaves of Col-0 and mutants infected with B. cinerea and A. brassicicola  was set at p < 0.05. Each assay contained three independent replicates.Mean and standard deviations are displayed as representative values for data in the figures. Analysis of variance (ANOVA) with Duncan’s test and Student’s The original contributions presented in the study are included in the article/YW and HZ designed the research. HZ did most experimental works and wrote the manuscript. ZY, ZL, and YS did experimental works and database analysis. XL, JW, and GZ did experimental works. YW supervised this project. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic developing since the late 2019 and early 2020 has caused thousands of deaths and has had an enormous impact on our health systems and economies. Thrombotic complications associated with coronavirus disease 2019 (COVID-19) have been described. Acute limb ischemia is associated with complications related to cytokine storm syndrome and acute respiratory distress syndrome. that can result in significant morbidity and mortality. However, limited published data is available regarding thrombosis in coronavirus disease 2019 (COVID-19). Here we are presenting 2 cases of COVID-19 infection complicated by arterial thrombosis in the form of acute limb ischemia. •COVID-19 pneumonia increases the incidence of acute limb ischemia.•Thrombotic complications associated with coronavirus disease 2019 can result in significant morbidity and mortality.•Patients with COVID-19 should receive pharmacologic thromboprophylaxis. On March 11, 2020, WHO declared coronavirus disease 2019 (COVID-19) as pandemic [The association of COVID-19 with coagulopathy has gained increasing interest recently. As per American Society of Hematology, some patients with severe coronavirus disease 2019 (COVID-19) have fulminant activation of coagulation and consumption of coagulation factors, which meets the criteria for disseminated intravascular coagulation as per International Society on Thrombosis and Hemostasis  which in22.180 years old patient, diabetic, hypertensive, presented to emergency department with complaints of shortness of breath and chest pain, with a discoloration and swelling of the right leg. Vital signs upon arrival were: heart rate at 113 per minute, blood pressure at 140/85 mmHg, oxygen saturation at 40% on room air and temperature at 38,6° Celsius.The patient had bilateral crackles on lung exam and absent right popliteal, dorsalis pedis and posterior tibial pulses and the foot was swollen, cyanotic, and cold .Fig. 1Cy3 (reference: 4.000–10.000/mm3), platelets 239.000/mm3 (reference: 150.000–400.000/mm3), potassium 5.1 meq/L , glucose 3,35g/l , creatinine 26,2 mg/l (reference: 6–13 mg/l), blood urea nitrogen 1,6 g/l , lactic acid 2,37 mmol/L (reference: 0.5–2.2 mmol/L), troponin 1150 ng/l (reference: less than 6 ng/l), D-dimer 35,2 (reference: less than 0.5), prothrombin time 67,%  1.24 (reference: less than 1), Creatine Phosphokinase (CPK) 2080 U/L  lactate dehydrogenase (LDH) 1497 U/L (reference: 140–271 U/L), C-reactive protein (CRP) 239 mg/L (reference: less than 10 mg/L), ferritin 1642 ng/L (reference: 12–300 ng/l), procalcitonin 2,88 ng/ml (reference: less than 2 ng/ml), calcium 9,1 mg/dl (reference: 8.6–10.3 mg/dl), and albumin 29 mg/l (reference: 35–50 mg/l).On initial laboratory evaluation, the following values were noted: hemoglobin 11.1 g/dl (reference: 12–16 g/dl), hematocrit 33,6% (reference: 36%–46%), white blood cells 27.680/mmChest X ray showed bilateral hazy infiltrates . ThoraciCovid-19 was diagnosed on the basis of reverse transcription polymerase chain reaction (RT- PCR) testing. Echocardiogram showed an ejection fraction of 55%. The patient was intubated and put under SDRA ventilation and was started on moxifloxacin, ceftriaxone, azithromycin, hydroxychloroquine, and therapeutic anticoagulation with heparin. He underwent a thigh amputation.2.269 years old patient, suffering from chronic obstructive pulmonary disease, presented to emergency department with complaints of shortness of breath and chest pain, with a discoloration and swelling of the left leg. Vital signs upon arrival were: heart rate at 130 per minute, blood pressure at 150/95 mmHg, oxygen saturation at 75% on room air and temperature at 38,1° Celsius.The patient had bilateral crackles on lung exam and absent left popliteal, dorsalis pedis and posterior tibial pulses and the foot was swollen, and cold.Electrocardiogram showed sinus tachycardia 140 per minute.3 (reference: 4.000–10.000/mm3), platelets 345.000/mm3 (reference: 150.000–400.000/mm3), potassium 4,8 meq/L , glucose 1,16 g/l , creatinine 7,25 mg/l (reference: 6–13 mg/l), blood urea nitrogen 0,56 g/l , lactic acid 2,37 mmol/L (reference: 0.5–2.2 mmol/L), troponin 9,5 ng/l (reference: less than 6 ng/l), D-dimer 12,96 (reference: less than 0.5), prothrombin time 78%  1.13 (reference: less than 1), Creatine Phosphokinase (CPK) 680 U/L  lactate dehydrogenase (LDH) 1040 U/L (reference: 140–271 U/L), C-reactive protein (CRP) 269 mg/L (reference: less than 10 mg/L), ferritin 854 ng/L (reference: 12–300 ng/l), procalcitonin 0,51 ng/ml (reference: less than 2 ng/ml), calcium 8,3 mg/dl (reference: 8.6–10.3 mg/dl), and albumin 33 mg/l (reference: 35–50 mg/l).On initial laboratory evaluation, the following values were noted: hemoglobin 15.1 g/dl (reference: 12–16 g/dl), hematocrit 42,5% (reference: 36%–46%), white blood cells 21.560/mmChest X ray showed bilateral hazy infiltrates. Thoracic and Abdominal CT angiography of the aorta with Iliofemoral runoff showed an occluded left anterior tibial artery and left peroneal artery with no flow to the foot .Fig. 4PrCovid-19 was diagnosed on the basis of reverse transcription polymerase chain reaction (RT- PCR) testing. Echocardiogram showed an ejection fraction of 60%. The patient was admitted to intensive care unit and put under high flow nasal oxygenation (Optiflow) and was started on azithromycin, hydroxychloroquine, and therapeutic anticoagulation with heparin. He underwent a thrombectomy of left common femoral artery, profunda femoris, superficial femoral artery, popliteal artery, anterior tibial artery, posterior tibial artery, and peroneal artery .Fig. 5Su3The COVID-19 pandemic is a fast-evolving situation. The spectrum of clinical manifestations of SARS-CoV-2 infection includes fever, myalgia, cough and dyspnea, and less frequently headache, diarrhea, nausea and vomiting . SeveritThe hypercoagulability of critically ill patients with COVID-19 became evident. In addition, some published epidemiologic data have shown increased thromboembolic events in those patients, such as unusual ischemic limbs and venous thromboembolism ,9. A higCui et al.  in a retAcute limb ischemia is a vascular emergency and can result in severe morbidity, including chronic pain, limb loss, and severe disability. A prompt diagnosis is a prerequisite for successful treatment. An observational study done in Italy revealed increased incidence of acute limb ischemia in patients with COVID-19 infections, they have noted the number of patients with acute limb ischemia during the peak of the pandemic has increased .The mechanism of thromboembolic complications associated with COVID-19 infection is not fully understood. COVID-19 related hypercoagulability is likely multifactorial-direct viral infection of the endothelial cell leading to diffuse endothelial inflammation, increased procoagulant factors such as factor VIII, von Willebrand factor, fibrinogen, and high inflammatory state associated with the cytokine storm leading to coagulation and fibrinolysis activation .The American Society of Hematology (ASH) recommends that all hospitalized patients with COVID-19 should receive pharmacologic thromboprophylaxis with LMWH or fondaparinux, unless bleeding risk exists, and full therapeutic-intensity anticoagulation in the appropriate clinical scenario .4We report 2 cases of arterial thrombosis in patients with COVID-19. Our case and review of literature reveals that health care providers should be aware of this unusual life-threatening manifestation of COVID 19 so that appropriate measures can be taken for the vascular emergency.Written informed consent was obtained from the patient for publication of this case report and any accompanying images.This is a case report.This study was not funded.Amine Bensaid: Stady concept, data collection, Data analysis, writing the paper. Imane Melhaoui: writing the paper. Oujidi Younes: Contributor. Inass Arhoun El Haddad: Data collection. Houssam Bkiyar: Supervision and data validation. Brahim Housni: Supervision and data validation.DR Amine Bensaid.Not commissioned, externally peer reviewed.No conflict of interest.


Neisseria meningitidis serogroup B and at a university where outbreak and response activities had not occurred. All eligible students at the two universities received the serogroup B meningococcal factor H binding protein vaccine (MenB-FHbp); 5.2% of students  at one university received MenB-4C. A total of 1,514 meningococcal carriage isolates were obtained from 8,905 oropharyngeal swabs from 7,001 unique participants. Whole-genome sequencing data were analyzed to understand MenB-FHbp’s impact on carriage and antigen genetic diversity and distribution. Of 1,422 isolates from carriers with known vaccination status , 1,406 (98.9%) had intact fHbp alleles (716 from MenB-FHbp-vaccinated participants). Of 726 isolates from MenB-FHbp-vaccinated participants, 250 (34.4%) harbored FHbp peptides that may be covered by MenB-FHbp. Genogroup B was detected in 122/1,422 (8.6%) and 112/1,422 (7.9%) isolates from MenB-FHbp-vaccinated and unvaccinated participants, respectively. FHbp subfamily and peptide distributions between MenB-FHbp-vaccinated and unvaccinated participants were not statistically different. Eighteen of 161 MenB-FHbp-vaccinated repeat carriers (11.2%) acquired a new strain containing one or more new vaccine antigen peptides during multiple rounds of sample collection, which was not statistically different (P = 0.3176) from the unvaccinated repeat carriers . Our findings suggest that lack of MenB vaccine impact on carriage was not due to missing the intact fHbp gene; MenB-FHbp did not affect antigen genetic diversity and distribution during the study period.Carriage evaluations were conducted during 2015 to 2016 at two U.S. universities in conjunction with the response to disease outbreaks caused by  Neisseria meningitidis (the meningococcus) is a major public health concern  caused by  concern . This ba concern , 3. RiskN. meningitidis  is commonly associated with carriage (–N. meningitidis serogroup B strain NZ98/254 (derived from the MeNZB vaccine) with porin A variable region 2 (PorA-VR2) variant 4 as the major antigen  cause most IMD cases worldwide, with B, C, and Y predominating in the United States , 4, and carriage –8. Quadrarriage –. Two proarriage –. MenB-FHarriage –, 11, cor antigen , 13. In iologist . Althougiologist , 16. Whiiologist , 8, 17.N. meningitidis serogroup B outbreaks nor MenB mass vaccination campaigns occurred  or undetermined genogroup  isolates either lacked or contained a truncated fHbp allele   analyzed, 635 (47%) were either capsule null (egative) . A higheegative) , was detegative) . All FHbegative) .10.1128/mBio.00855-21.2TABLE S1Table S1, PDF file, 0.03 MB.Number of carriage isolates by genogroup. Download Copyright © 2021 Marjuki et al.2021Marjuki et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the fHbp allele, with 28 unique FHbp peptides (19 belonging to A/v2-3 and nine to B/v1) being detected, and had higher sequencing diversity than other genogroups. FHbp B/v1 peptides were detected among 57/225 (25.3%) genogroup B isolates; all remaining genogroup B isolates contained FHbp A/v2-3. FHbp A05/3.45 was detected in 21/225 (9.3%) genogroup B isolates, and FHbp B24/1.1 was detected in 17/225 (7.6%) genogroup B isolates  contained an intact isolates .nhbA allele was detected in 1,331 (99.6%) carriage isolates, with 90 unique NhbA peptides being identified  carriage isolates had intact entified . NadA-3.entified .10.1128/mBio.00855-21.4TABLE S3N. meningitidis carriage isolates. Download Table S3, PDF file, 0.09 MB.Distribution and diversity of NadA among Copyright © 2021 Marjuki et al.2021Marjuki et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the fHbp and nhbA intact. Ninety-two (6.9%) carriage isolates contained all three intact fHbp, nhbA, and nadA genes, of which 44 (47.8%) belonged to capsular genogroup B.Overall, there were 1,320 (98.7%) isolates with both porA alleles that belonged to 207 PorA types, and 9/1,316 (<1%)  contained PorA-VR2 variant 4, included in the MenB-4C vaccine  harbored intact  vaccine .N. meningitidis isolates  were recovered from participants with known vaccination status  of students at OR. A total of 1,422 n status , with 7210.1128/mBio.00855-21.5TABLE S4Table S4, PDF file, 0.03 MB.Number of isolates from participants with known MenB vaccine records. Download Copyright © 2021 Marjuki et al.2021Marjuki et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the fHbp alleles: 716/1,422 (50.4%) from MenB-FHbp-vaccinated participants, 42/1,422 (3.0%) from MenB-4C-vaccinated participants, and 648/1,422 (45.6%) from unvaccinated participants. The distribution of FHbp subfamilies in MenB-FHbp-vaccinated and unvaccinated groups was analyzed for all three universities as well as each university  had intact iversity . OverallfHbp allele or contained a truncated fHbp allele, including nine isolates from MenB-FHbp-vaccinated participants and four isolates from unvaccinated participants at RI-1 and two isolates from OR (one each from MenB-FHbp-vaccinated and unvaccinated participants). There was no statistically significant difference in FHbp peptide distributions between vaccinated and unvaccinated participants among genogroup B isolates and non-B genogroups from each university.The distribution of FHbp peptides was assessed among carriage isolates from MenB-FHbp-vaccinated and unvaccinated participants at RI-1 and OR . OverallWhile FHbp B01/1.55 was not detected in any isolate in this study, FHbp A05/3.45 was present in 12 of 726 (1.7%) isolates (11 genogroup B and one undetermined genogroup) from MenB-FHbp-vaccinated participants (nine from RI-1 and three from OR), all of which were from six MenB-FHbp-vaccinated participants (each received either one or two vaccine doses). Other FHbp peptides , shown to be covered by MenB-FHbp –24, were–P = 0.3176).Of 194 repeat carriers, 161 (83.0%) received MenB-FHbp, 3 (1.5%) received MenB-4C, and 30 (15.5%) did not receive a vaccine. Among 161 MenB-FHbp-vaccinated repeat carriers, 143 (88.8%) had 302 isolates that retained the same strain genotype and 18 (11.2%) had 40 isolates that acquired a new strain genotype . Among t10.1128/mBio.00855-21.6TABLE S5N. meningitidis isolates recovered from repeat carriers who carried new strains during the carriage evaluation period. Download Table S5, PDF file, 0.1 MB.Sequence typing profiles of Copyright © 2021 Marjuki et al.2021Marjuki et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the P < 0.0001) and genogroup B isolates (P = 0.0225). Additionally, of the 42 isolates that acquired a new strain genotype, the FHbp peptide prevalence between the detected strains in the previous round and newly acquired strains in the following round changed from B09/1.13  to B16/1.4  and from p0010 and p0024  to p0021  for NhbA  carried by MenB-FHbp-vaccinated repeat carriers, 32 unique FHbp peptides were detected, with B16/1.4  being the most prevalent, followed by B09/1.13 . Within the 302 isolates that retained the same strain genotype, six each (2.0%) harbored FHbp A05/3.45 or B24/1.1. Among the 60 isolates (10 genogroup B isolates) from unvaccinated participants, 13 unique FHbp peptides were detected, with B16/1.4  being most prevalent. There was a statistical difference in FHbp peptide distribution between vaccinated and unvaccinated repeat carriers among all isolates  of carriage isolates. We found an equal proportion of carriage isolates with an intact fHbp gene recovered from vaccinated (95% received MenB-FHbp) and unvaccinated participants. Statistical analysis showed no significant difference in the distribution of FHbp subfamilies or peptides between vaccinated and unvaccinated populations, suggesting that the vaccine does not impact the overall FHbp diversity and distribution.Analysis of whole-genome sequencing data has allowed us to understand MenB vaccine antigens and assess the impact of MenB-FHbp on their genetic diversity and distribution in U.S. meningococcal carriage. Almost all carriage isolates (99%) contained an intact isolates , but theBordetella pertussis following the introduction of pertussis vaccines, possibly due to vaccine selective pressure   , 38 thanOverall, similar FHbp peptide distributions were observed among carriage isolates from both vaccinated and unvaccinated participants during the study period. Additional investigations over a longer period are warranted to adequately evaluate the vaccine impact on carriage.N. meningitidis serogroup B outbreak and response activities occurred. A total of 1,514 meningococcal isolates  were recovered from 8,905 oropharyngeal swabs collected from 7,001 unique individuals . N. meningitidis species was determined using real-time PCR targeting sodC .Isolates included in this study were collected during February 2015 to March 2016 from meningococcal carriage evaluations at three U.S. universities  following vaccination using standardized methods as previously described , 8, 19. ing sodC , and sering sodC , 41. A tNeisseria meningitidis serogroup B carriage in institutional settings during an outbreak.”These evaluations were considered public health evaluations and did not require CDC institutional review for human subjects’ protection. Both evaluations were covered under project determination numbers 2015–6436 and 2015–6442 for “Evaluation of De novo short-read assembly was carried out using SPAdes 3.7.0 (cnl) . Illumina reads were trimmed with cutadapt  to removes 3.7.0  with thees 3.7.0 ; isolate.0 (cnl) . Genome .0 (cnl)  against database  to deterdatabase . All unidatabase , 48, 49.While 1,514 carriage isolates were obtained, only one isolate from each participant who carried the same meningococcal strain in more than one round (repeat carriers) was included in the analysis to assess the MenB vaccine antigen diversity and distribution among the carriage isolates circulating in the three universities, resulting in a total of 1,337 isolates.To compare MenB vaccine antigen distribution between vaccinated (received ≥1 dose of MenB-FHbp or MenB-4C 14 days prior to sample collection) and unvaccinated participants, all isolates from repeat carriers were included even if they appeared to be the same strain genotype (CC:ST:PorA:FetA); however, participants with unknown MenB vaccination records were excluded from the analysis (92 isolates from RI-1 and OR), resulting in a total of 1,422 carriage isolates. For phylogenetic analysis of MenB vaccine antigens, multiple-sequence alignment of peptides was generated by ClustalW  with CLCN. meningitidis serogroup B or non-N. meningitidis serogroup B. Isolates negative for both subfamilies A and B were excluded from this test due to being a low proportion (0.9%) of the overall isolate collection. Chi-squared goodness-of-fit tests were used to test for changes in distribution among N. meningitidis serogroup B and non-N. meningitidis serogroup B isolates. A Bonferroni correction was applied to correct for multiple comparisons. To assess proportions between vaccinated and unvaccinated repeat carriers who acquired a new meningococcal strain, a Fisher’s exact test was performed; FHbp peptide distributions in all isolates and genogroup B isolates among these groups were analyzed using a likelihood ratio chi-squared test.Statistical analysis was performed using SAS version 9.4 . Fisher’s exact test was used to assess changes in the distribution of FHbp subfamilies and peptides in isolates recovered from vaccinated and unvaccinated participants, stratified by university and whether the isolate was PRJNA533315.Sequence reads are available under NCBI BioProject no.


FallsTalk is a one-month evidence-based falls prevention (FP) program that focuses attention on causes of an individual’s falls and encourages new FP behaviors. We translated the program for family caregivers of persons with cognitive impairment or dementia (PwCID) to administer to the PwCID and examined the number of new FP behaviors (#newFPBs) reported during the intervention period by the Caregiver. Thirty-four Dyads (Caregiver+PwCID) were trained to conduct brief daily FP discussions together using paper (FTCGnoTech) or computerized  guidance. Dyads had FallsTalk training, daily discussions and weekly check-in calls. FTCGTech included discussion suggestions tailored to Caregiver concerns. To examine the use of technology, Poisson regression models compared #newFPBs between FTCGnoTech and FTCGTech and included covariates age (<80 or >=80), Mini-Mental Status Exam (MMSE >25 or <=25) and interactions. To evaluate the influence of Caregiver participation, #newFPBs reported by 115 non-demented clinical trial participants (no Caregiver- FT-ClTrNoCG) were compared with the Caregiver outcomes. Dyads using technology reported significantly more #newFPBs (MeanFTCGnoTech=5.34(SEM=0.68), MeanFTCGTech=8.46(SEM=0.76); p=.004) during the intervention month. A significant interaction was observed whereby Dyads with MMSE<=25 using technology, reported significantly more #newFPBs than the non-technology group (MeanFTCGnoTech=4.23(SEM=0.72), MeanFTCGTech=9.01(SEM=0.90); p=.047). Caregiver (n=34) involvement substantially increased #newFPBs (MeanFT-ClTrNoCG=1.39(SEM=0.15), MeanCaregiver=7.21(SEM=0.49); p<.0001), independent of technology. Across studies, participants or Caregivers for those with MMSE<=25 and <80yo reported significantly more #newFMBs (Mean=4.38(SEM=0.55) than those 80+yo (Mean=2.06(SEM=0.30); p=.0026). FallsTalk Caregiver provides an effective means to promote new Dyad FP strategies. The influence of Caregiver involvement and technology show promise in encouraging behavioral change to prevent falls.


Escherichia coli and Klebsiella pneumoniae, as compared to 3GC-susceptible isolates of either species.Carbapenems are considered the drugs of choice for first-line treatment of severe infections caused by carbapenem-susceptible, extended-spectrum β-lactamases (ESBL)-producing Enterobacterales, while piperacillin-tazobactam has been recommended as an alternative for treatment of non-severe infections. Temocillin is stable to ESBL and AmpC enzymes and may thus represent another treatment option. This study assessed the in vitro activity of piperacillin-tazobactam and temocillin against third-generation cephalosporin (3GC)-resistant One hundred and nine isolates from hospitalized patients with bloodstream and urinary tract infections were tested. All isolates were collected during the resistance surveillance study of the Paul-Ehrlich-Society for Chemotherapy in 2016/17. Minimum inhibitory concentrations (MICs) were determined by broth microdilution according to the standard ISO 20776-1 and interpreted using EUCAST clinical breakpoints (version 11.0).E. coli, n=58; K. pneumoniae, n=21) were 3GC-resistant and 30  were 3GC-susceptible. Susceptibility to piperacillin-tazobactam was detected in 93.3% of 3GC-susceptible isolates (for both E. coli and K. pneumoniae) and in 79.3% and 57.1% of the 3GC-resistant E. coli and K. pneumoniae, respectively. In contrast, 3GC-susceptible isolates were 100% susceptible to temocillin as were 94.8% and 90.5% of the 3GC-resistant E. coli and K. pneumoniae, respectively.Seventy-nine isolates (E. coli and K. pneumoniae from bloodstream and urinary tract infection samples, with susceptibility rates exceeding those of piperacillin-tazobactam.In conclusion, temocillin demonstrated potent in vitro activity against carbapenem-susceptible, 3GC-resistant  Escherichia coli and Klebsiella pneumoniae is most commonly mediated by extended-spectrum β-lactamases (ESBLs), but also occurs through other mechanisms like plasmid-encoded AmpC-type enzymes . Mo enzymes , [2], ) and two were ceftazidime-resistant only (cefotaxime-susceptible [S+I]).Meropenem inhibited all isolates at the lowest concentration tested . Seventy-nine isolates were 3GC-resistant  and the number and percentage of isolates classified as susceptible (S or I) or resistant were calculated.MIC distribution data of temocillin and piperacillin-tazobactam are presented in Table 1 E. coli and K. pneumoniae. MIC50/90 values of piperacillin-tazobactam and temocillin were ≤1/4 mg/L and 4/16 mg/L, respectively, for E. coli, and ≤1/8 mg/L and 2/8 mg/L, respectively, for K. pneumoniae. One isolate each of E. coli and K. pneumoniae had a piperacillin-tazobactam MIC of ≥128 mg/L. MICs of ceftazidime for both isolates were 1 mg/L as compared to MICs of ≤0.25–0.5 mg/L for the other 28 3GC-susceptible isolates.Susceptibility to piperacillin-tazobactam (MIC≤8 mg/L) and temocillin (MIC≤16 mg/L) among the 30 3GC-susceptible isolates was 93.3% and 100%, respectively, for both E. coli and K. pneumoniae to the other antibiotics tested are displayed in E. coli were observed for ampicillin (53.3%), cotrimoxazole (26.7%), and amoxicillin-clavulanic acid (20%), while the highest level of drug resistance in 3GC-susceptible K. pneumoniae, except for ampicillin, was observed for fosfomycin (33.3%). Two 3GC-susceptible K. pneumoniae were colistin-resistant.Susceptibility data of the 3GC-susceptible E. coli was 79.3% (95% CI: 68.9–89.7%) versus 94.8% (95% CI: 89.1–100%), respectively, and among 3GC-resistant K. pneumoniae 57.1% (95% CI: 44.4–69.8%) versus 90.5% (95% CI: 83.0–98.0%), respectively. MIC50/90 values of piperacillin-tazobactam and temocillin were 2/32 and 8/16 mg/L mg/L, respectively, for E. coli, and 8/≥128 mg/L and 8/16 mg/L, respectively, for K. pneumoniae. Seventeen 3GC-resistant isolates  were resistant to piperacillin-tazobactam, but susceptible to temocillin, while one E. coli isolate was temocillin-resistant, but susceptible to piperacillin-tazobactam. Two isolates of either species were resistant to both antimicrobials  were detected for levofloxacin, tobramycin and fosfomycin in 3GC-resistant K. pneumoniae. One 3GC-resistant isolate each of E. coli and K. pneumoniae was colistin-resistant, and two 3GC-resistant E. coli were fosfomycin-resistant.Susceptibility data of the 3GC-resistant, carbapenem-susceptible E. coli and K. pneumoniae has become widespread in all parts of the world. According to data of the European Antimicrobial Resistance Network (EARS-Net), investigating invasive isolates, resistance to 3GC in E. coli rose from 1.7% in 2002 to 15.1% in 2019. 3GC resistance also increased in K. pneumoniae. EARS-Net reported an overall resistance rate of 31.3% for 2019, with extremely large differences in the level of resistance between individual countries (to >60%)  and one temocillin-resistant [MICs 32–64 mg/L]) without resistance to other β-lactams, found mutations in several genes, including a porin-encoding gene (ompD-like) and genes encoding for transport/membrane proteins . T. TE. coleumoniae . Temocillsewhere , 15], [, [E. col Table 2 , but the Table 2 . Seventy Table 2 . Thus, oic shock . It musthttps://doi.org/10.5061/dryad.931zcrjkc [Data for this article are available from the Dryad Repository: 31zcrjkc The investigation of the susceptibility of the test organisms to temocillin was supported by a grant from Eumedica S/A, Manage, Belgium, to Antiinfectives Intelligence GmbH.MK is a partner and CEO of Antiinfectives Intelligence GmbH, a research organization providing services to pharmaceutical companies. YP and GW declare that they have no competing interests.


Streptomyces (68%), Micromonospora (6%), and Nocardiopsis (3%) are dominant producers of secondary metabolites. Additionally, alkaloids (37%), polyketides (33%), and peptides (15%) comprise the largest proportion of natural products with mostly antimicrobial activity and cytotoxicity. Furthermore, the data analysis and clinical information of SMs have been summarized in this article, suggesting that some of these actinomycetes with multiple host organisms deserve more attention to their special ecological status and genetic factors.The actinomycetes have proven to be a rich source of bioactive secondary metabolites and play a critical role in the development of pharmaceutical researches. With interactions of host organisms and having special ecological status, the actinomycetes associated with marine animals, marine plants, macroalgae, cyanobacteria, and lichens have more potential to produce active metabolites acting as chemical defenses to protect the host from predators as well as microbial infection. This review focuses on 536 secondary metabolites (SMs) from actinomycetes associated with these marine organisms covering the literature to mid-2021, which will highlight the taxonomic diversity of actinomycetes and the structural classes, biological activities of SMs. Among all the actinomycetes listed, members of  Actinomycetes are Gram-positive bacteria with a GC-rich linear genome and have proven to be a rich source of secondary metabolites (SMs) of broad structural diversity and biological properties . The oceThe objective of this article is to provide an overview of the natural products from actinomycetes associated with marine animals, marine plants, macroalgae, cyanobacteria, and lichens. The present review was not only summarizing the structural classes and biological activities of SMs but also highlighted the taxonomic diversity of actinomycetes, as well as the data analysis of integrated above information. Some of these metabolites with excellent activity are expected to become new drugs such as antibiotics, antineoplastic drugs, or anticancer drugs. Therefore, actinomycetes with multiple host organisms deserve more attention to their special ecological status and genetic factors.Streptomyces, Micromonospora, Microbacterium, and Nocardiopsis were abundant , respectively indole, another known compound indole-3-acetic acid (S16) was discovered from this strain indole (tnam Sea . In addis strain .73) and isoquinocycline B (74)  showed good antibiotic activity not only against the Gram-positive strain S. aureus SH1000, but also the Gram-negative strains efflux knockout (KO) mutant strains of K. pneumoniae ATCC10031 and A. baumannii ATCC 17978. It was also active against the human liver cancer cell line HepG2 with an IC50 of 13.3 µM ..Callyspo79) (S38), and aerugine (80) (S39) and furan-2-carboxamide (S40) from Streptomyces sp. OUCMDZ-1703 associated with a soft coral sample collected from the South China Sea. Thiazole derivatives 79 and 80 displayed moderate antibacterial activity against S. aureus and three methicillin-resistant strains MRSA082, MRSA111, and MRSA234 anthraquinone derivatives, urdamycinone E (in (134)  were ide E (135) , the pos50 μg/mL ,95.136–141) (Streptomyces sp. CMS JV M18_3 [136–139) has great antibacterial activities against MRSA and vancomycin-resistant Enterococcus faecium (VREF). In addition, compounds 136–139 were active against HCT-116 human colon carcinoma [141) displayed anti-biofilm activity inhibiting Staphylococcus aureus biofilm formation, and compound 140 exhibited antimicrobial activities against some Gram-positive bacteria [Six dihydroquinone derivatives 136–141)  were iso6–141  wearcinoma . SF2415Bbacteria ,98.142) and B (143) (Nocardiopsis sp. KMF-002 was cultivated from an unidentified dark purple marine sponge. Nocatrione A (142) showed a significant protective effect against UVB irradiation in both NHDF cell lines, whereas nocatrione B (143) was active against UVB only in a specific NHDF cell line [In 2014, Min Cheol Kim et al. reported isolation and identification of two novel tetracenedione derivatives nocatriones A ( B (143)  from Nocell line .Actinokineospora sp. EG49 cultivated from the marine sponge Spheciospongia vagabunda afforded two new actinosporin analogs actinosporins C (144) and D (145) (146) and B (147) ( D (145) . At 1.25 B (147)  were als148)  [Microluside A (148)  is a uniectively . In 2015in (S72) .149) (S73), and a related analog (−)-BE-52440A (150) -BE-52440A (150) showed cytotoxicity against NB4 and HL-60 cells with IC50 values of 1.7 and 1.8 μM, respectively. Naquihexcin A (149) bears a rare unsaturated hexuronic acid moiety and could inhibit the proliferation of an adriamycin-resistant human breast cancer cell line MCF-7 ADM with IC50 = 16.1 μM, indicating that the unsaturated hexuronic acid moiety could enhance the activity against the cancer cells [Three S-bridged pyranonaphthoquinone dimers naquihexcins A (149)  and B (S0A (150)  were proer cells .S74, identified as 3-hydroxy-2-methyl-4H-pyran-4-one , was isolated both from the Streptomyces sp. SBT348 and Rhodococcus sp. UA13 [S75 was discovered from the co-culture of sponge-derived Saccharomonospora sp. UR22 and Dietzia sp. UR66 [151–153) (Nocardiopsis sp. HB-J378 associated with Theonella sp. Nocardiopsistin B showed the best anti-MRSA activity with the same MIC (3.12 μg/mL) as that of chloramphenicol, whereas nocardiopsistins A and C have a moderate anti-MRSA activity (MIC = 12.5 μg/mL) [151–153), it was found that the ketone functional group at C-4 could enhance the anti-MRSA activity, while the hydroxyl group at C-3 weakened activity.Compound sp. UA13 ,45. Compsp. UR66 . In 2018151–153)  separate5 μg/mL) . On compS76) was first isolated from Streptomyces rochei MB037 associated with marine sponge Dysidea arenaria collected at Yongxin Island in the South China Sea. And the co-culture with fungus Rhinocladiella similis 35 derived from gorgonian could enhance its production [154), together with three known actinosporins C, D, and G   exhibited potent antitrypanosomal activity and growth inhibitory activity towards Trypanosoma brucei strain TC221 [7-methoxy-2,3-dimethylchromone-4-one   were obtin TC221 .156 and 157)   were pro[158–160  were iso and 162  showed iectively .146, 144) were isolated from the axenic cultures of strain EG49. Actinosporin A showed anti-trypanosomal activity and actinosporin C exhibited antioxidant activity. New actinosporins E–H  (165)  (S78) [Actinosporins A and C   were pro4) (165)  and the  B (166)  (plant g167) (S79) with fully saturated eight-membered lactone ring were reported in 1991 from Streptomyces sp. PG-19 collected on the surface of Cortez gorgonian octocoral Pacifigorgia sp. Octalactin A demonstrated significant in vitro cytotoxicity toward B-16-F10 murine melanoma (IC50 = 7.2 × 10−3 µg/mL) and HCT-116 human colon tumor (IC50 = 0.5 µg/mL) [Isolation of two novel compounds Octalactins A (167)  and B (S5 µg/mL) .S80) was produced by a marine actinomycete Micromonospora sp. strain A5-1 obtained from soft coral Scleronephthya sp. in the East China Sea [Streptomyces sp. OUCMDZ-1703† associated with a soft coral collected from the South China Sea led to the discovery of two new chlorinated polyketides strepchloritides A and B (168 and 169) (S41). Polyketides 168 and 169 showed moderate cytotoxicity against MCF-7 tumor cells [A novel analog of jadomycin B, 7b,13-dihydro-7-O-methyl jadomycin B (hina Sea . Streptoand 169) , togetheor cells .S81) and two known anthracycline derivatives  were produced by coral-associated Streptomyces sp. SCSIO 41399. Compound 170 (Aranciamycin K (ound 170  exhibite171) and anthracimycin (172)  with MIC values less than 0.03 µg/mL. And anthracimycin B was also active against these four Gram-positive bacteria. In addition, anthracimycin displayed anti-tubercular activity against Mycobacterium tuberculosis [A novel gram-positive antibiotic anthracimycin B (in (172)  were isorculosis .173)  and HePG2 (hepatic carcinoma) in vitro [1-hydroxy-1-norresistomycin (HNM) (173)  was prodin vitro .174–176)   were rep25 μg/mL .177)   was isolhrocytes ,110.178)   was founlomerase ,111.Streptomyces sp. #N1-78-1 from sea squirt Ecteinascidia turbinata in Puerto Rico led to the purification of bisanthraquinones 1 and 2 , as well as derivative 3 (181) (Staphylococcus aureus) and VRE , and these three compounds displayed cytotoxic activity against HCT-116 cells [The isolation of  3 (181) , the deh16 cells ,112.182, 183, S83, and S84) were produced by a strain of Micromonospora sp. derived from a Brazilian endemic ascidian Eudistoma vannamei. Compounds 182 and 183 . Halomadurones C (184) and D (185) (186)   showed p5) (186)  was also strains .187–190) and nahuoic acid A (191)  with an unprecedented carbon skeleton was the first natural product inhibiting the SETD8 lysine methyltransferase and the first selective SETD8 inhibitor. Compounds 187–191 showed weak antibiofilm activity against Shewanella onedensis MR-1 biofilm [S87, S88, 192–194). Compounds E-G (192–194)   were sep biofilm . In 2017192–194)  had weaksubtilis .Streptomyces coelicoflavus strain HQA809, which is isolated from sea squirt Styela clava, produced germicidin (195) and 6-isopropyl group-3-ethyl-4-hydroxy-2-pyrone (196)  . Both twa salina .Streptomyces sp. PTY087I2 associated with styela canopus collected from Bastimentos Park, Bocas del Toro, Panama produced three naphthoquinone derivatives granaticin (197), granatomycin D (198), and dihydrogranaticin B (199)  . Co-cultathogens ,118.200–204)  suppressed the proliferation of cancer cell lines, and metabolites 203 is the most active compound with IC50 values ranging from 0.59 to 3.39 mM. The 11-hydroxycurvularins 200 and 201 also showed antibacterial activity inhibiting the growth of Escherichia coli [205 . And the known metabolite 301 (Five curvularin macrolides (200–204)  were isohia coli . Compounoli [205 , which wlite 301  with ant206), ochromycinone (207), and X-14881 C (208), together with a new angucyclines saccharothrixmicine A (209) (Saccharothrix espanaensis An 113 obtained from a marine mollusk specimen (Anadara broughtoni), which was collected from Peter the Great Bay, Sea of Japan, Russia. Compounds 206–208 showed significant activity against C. albicans, B. subtilis, E. faecium, S. aureus, and Xanthomonas sp. pv. badrii. And Compound 209 exhibited activity towards Candida albicans and Xanthomonas sp. pv. Badrii [S89) and F (S90), together with gilvocarcins M (S91) and V (S92), have been isolated from an unidentified tunicate-associated Saccharopolyspora sp. SS081219 JE-28 [Three known analogs X- 14881 E ( A (209) , were pr. Badrii ,121. Mac19 JE-28 ,77.210) and I (211) were reported together with known violapyrones B (212) and C (213)  showed growth inhibitory activity against cancer cell lines at concentrations less than 26.12 μg/mL. Wherein compound 210 showed the highest cytotoxic activity against the HCT-15 cell line with a GI50 value of 1.10 μg/mL. Additionally, violapyrones B and C were demonstrated to have antibacterial activities. Therefore, it may be noteworthy that each compound has structural similarities, but showed different activities. The results suggested that the length of the aliphatic side chain and the position of the methyl group affected the activity. Furthermore, violapyrones having an isomethyl group in the alkyl side chain showed better activity than others [Isolation of two novel 3,4,6-trisubstituted α-pyrone derivatives violapyrones H ( C (213) , from Stn others .214) and PM100118 (215)   from StrTCC10231 .216, 217) (S93–S97) were produced by the sea anemone-derived Streptomyces sp. ZZ406. New compounds 216 and 217 showed potent activity in inhibiting the proliferation of different glioma cells and downregulating the expressions of glioma metabolic regulators. Compound 216 was active against the proliferation of different glioma cells with IC50 values of 4.7 to 8.1 μM, high selectivity index (>12.3 to 21.3), and good stability in human liver microsomes [S98) and the known angucyclinone PD116740 (126) were isolated from the sea urchin-derived Streptomyces sp. HDa1 [Two new compounds   and fivecrosomes . A novelsp. HDa1 .11 (218) and Q12 (219)  were separated from the marine gastropod mollusk Batillaria zonalis-associated Streptomyces sampsonii SCSIO 054. In addition, four known anthraquinones chrysophanol (S101), 4-acetylchrysophanol (S102), islandicin (S103), and huanglongmycin A (S104) were also discovered. Julichrome Q12 (219) was found to display antibacterial activity against Micrococcus luteus and Bacillus subtilis with MICs of 2.0 and 8.0 μg/mL. What’s more, compounds 218, 220–222  , along w 220–222  also sho64 μg/mL .223–225) (50 0.63 μg/mL), and all three novel metabolites exhibited significant cytotoxicity against the 39 human cancer cell lines [Further investigation for metabolites of this strain has led to the isolation of three additional novel cytotoxic metabolites designated as halichoblelide A–C (223–225) . Halicholl lines ,126.226)  [Ochoa et al. reported the isolation of a new glycosylated polyketide phocoenamicin (226)  in 2017, 2.6 μM) .Most peptides from actinomycetes are circular and contain further rare structural elements, such as chromophore or unusual amino acids.Streptomyces sp. DA18 was separated from marine sponge Craniella australiensis collected at Sanya Island in the South China Sea, from which diketopiperazines (DKPs)    were disactivity .230)  and Trypanosoma brucei brucei (IC50 = 0.0032 μM). Additionally, it was active against 293T kidney epithelial cells (IC50 11.24 µM) and J774.1 macrophages (IC50 < 0.10 µM) [The cyclic depsipeptide valinomycin (230)  was isol0.10 µM) .231) (Nocardiopsis strain HB383 [232) . The compound displayed weak cytotoxic activity against human cervical carcinoma HeLa cells with an IC50 value of 49 μM [A diketopiperazine (231)  with weain HB383 . The new83 [232)  was puriof 49 μM .233) and JBIR-35 (234)   from Strd 2.5 mM .S106) and JBIR-57 (S107) were reported in 2011 from the new isolate Streptomyces sp. SpD081030SC-03, which was obtained from an unidentified sponge collected in Ishigaki, Okinawa, Japan [Isolation of two new peptides JBIR-56   were discovered in 2011 from Verrucosispora sp. strain WMMA107, which was separated from Chondrilla caribensis f. caribensis . 22′-Deoxythiocoraline (236), thiochondrilline C (237), and 12′ -sulfoxythiocoraline (238)  , which wne (238)  showed sectively .Streptomyces sp. strain RV15 was reported to produce four new cyclic lipopeptides cyclodysidins A–D (S110–S113) in 2012 [239 and 240) (S114), were isolated from Streptomyces M1087 associated with an unidentified sponge. The new compounds 239–240 exhibited weak inhibition against the recombinant enzyme sortase B with EC50 values of 88.3 and 126.4 µg/mL [A sponge-derived  in 2012 ,133. Twoand 240) , along w.4 µg/mL .Streptomyces sp. NIO 10068 derived from a sponge collected from the western coast of India produced linear dipeptides proline–glycine (S115) and N-amido-α- proline (S116) [241)  with MIC values of 0.25–0.5 μg/mL [e (S116) . Kocurin6) [241) , a new m.5 μg/mL ,137.242) (S117) in 2015, from sponge-associated Streptomyces sp. LS298. Quinomycin G (242) with a terminal double bond in one of the Ser groups exhibited moderate antibacterial activities against Staphylococcuse pidermidis, S. aureus, Enterococcus faecium, and E. faecalis with MIC values ranging from 16 to 64 μg/mL. In addition, it showed potent anti-tumor activities and the highest activity was observed against the Jurkat cell line (human T-cell leukemia) with an IC50 value of 0.414 μM [Xin Zhen et al. reported isolation and identification of two new metabolites quinomycin G (242)  and cycl0.414 μM .243) (Streptomyces sp. SBT348 exhibited significant cytotoxicity towards the human promyelocytic HL-60 and the human colon adenocarcinoma HT-29 cell lines [244) (S118) were isolated from Streptomyces sp. GKU 220 is associated with a marine sponge sample collected in Andaman sea, Ranong, Thailand. Rakicidin F (244) showed growth inhibitory activity against B. subtilis and E. coli at the dosage of 25 μg per disk [A new cyclic dipeptide petrocidin A (243)  was discll lines . New cyces [244)  and knowper disk .245)   was repo μg/disk . Four disp. G246 . And thr246 [246  and S120sp. G248 .247–250) and actinomycin D (251) (Streptomyces sp. LHW52447 associated with Phyllospongia foliascens obtained from the Xisha Islands in the South China Sea. Actinomycins D1 (247) and D2 (248) introduced an oxazole unit into the central phenoxazinone chromophore and exhibited more potent activities against three strains of MRSA with MIC values of 0.125–0.25 μg/mL than that of actinomycins D3–D4 (MIC = 0.5–1.0 μg/mL), which indicated that the incorporation of the oxazole unit would enhance the antibacterial activity. In addition, the cytotoxicity evaluation against human lung WI38 embryonal fibroblasts suggested that the incorporation of oxazole unit could decrease the cytotoxicity of actinomycins on human normal cells [Four new D-type actinomycin analogs actinomycins D1-D4 ( D (251)  were disal cells . The SARal cells ,142.Streptomyces sp. Call-36 isolated from sponge Callyspongia sp. collected in the Red Sea was reported to produce a new diketopiperazine actinozine A (252), cyclo(2-OH-D-Pro-L-Leu) (253), cyclo(D-Pro-L-Phe) (254) (L-Pro-L-Phe) (S123). Compounds 252 and 253 displayed potent activity against S. aureus and were moderately active against C. albicans. Compound 254 exhibited moderate and selective activity against HCT-116 with an IC50 of 32.7 µM, while cyclo (L-Pro-L-Phe) (S123) was inactive, indicating that the D/L configuration of Pro had an important effect on the activity [e) (254) , and cycactivity .255) (Nesterenkonia sp. MSA31 and active against multidrug-resistant Pseudomonas aeruginosa by inhibiting the phenotypic expression of virulence factors [256–258)   was isol factors . Three a256–258)  were obt235) is a thiodepsipeptide antitumor antibiotic isolated from Micromonospora sp. L-13-ACM2-092 is associated with a soft coral collected in the Indian Ocean off the coast of Mozambique. Thiocoraline had an inhibitory effect on DNA polymerase α. In addition, it displayed potent cytotoxicity and strong activity against Gram-positive bacteria [Thiocoraline   (229), bacillusamide B (261) (L-Pro-L-Leu) (246), and cyclo (L-Pro-L-Ile) (262)   from a sand MSSA ,147. Fou B (261) , cyclo (e) (262) , were send MCF-7 ,72.263–265)  (263–265)  was repoell line .266, 267) (S127–S129) were discovered from Streptomyces sp. CNB-091 obtained from the surface of jellyfish Cassiopeia xamachana collected in the Florida Keys. Salinamides A and B exhibited moderate antibiotic activity against Gram-positive bacteria. Additionally, the results of phorbol ester-induced mouse ear edema assay showed that salinamides A and B displayed significant topical anti-inflammatory activity using [268)   and sality using ,150. In ng [268) , a new b269–271  was separated from Micromonospora sp. ML1 isolated from a mollusk collected from the Indian Ocean coast of Mozambique [272) and H (273)  inhibitory activity with IC50 values of 7.50 and 7.37 μmol/L, respectively [Three known diketopiperazines 269–271  producedolyticus . Thiocorzambique . Limazep H (273)  were disectively .S130 and the known valinomycin (230) in 2018, from sea anemone-associated Streptomyces sp. ZZ406. Valinomycin (230) was active against the proliferation of different glioma cells and downregulating the expressions of glioma metabolic regulators [Streptomyces sp. strains 22 and 34 that have been mentioned above. Compound 274    was sepaof 31 μM ,154.276, 277, S131–S133) were isolated from Streptomyces sp. (ZJG1) cultivated from stony corals collected in the South China Sea. Compound 277 (276 (Five sesquiterpenes (ound 277  showed g277 (276  exhibiteS134) and B (278)   was repos aureus .Streptomyces sp. RKBH-B7 is associated with octocoral Eunicea. Guanahanolide A (279)   showed m280) (S135), two novel eunicellin diterpenoids, were reported in 2020 from the culture of Streptomyces albogriseolus SY67903 associated with the gorgonian Muricella sibogae collected at the South China Sea. Microeunicellol A exhibited cytotoxicities against several human cancer cell lines [Microeunicellols A (280)  and B (Sll lines .281–283)   were disof 30 μM .284)  , a novel2 μmol/L .285) (S136) were isolated from sponge-associated Streptomyces sp. RM66. Manadoperoxide H exhibited antitrypanosomal activity against Trypanosoma brucei rhodesiense with an IC50 value of 0.375 μg/mL [Manadoperoxide H (285)  and acan75 μg/mL .S137) was purified from Micrococcus luteus R-1588-10 associated with sponge Xestospongia sp. collected at Noumea, New Caledonia. Additionally, the previously known synthetic 2,4,4′-trichloro-2′-hydroxydiphenylether (286)   was alsoalbicans ,160.287) (Streptomyces sp. (LA3L2). Two known compounds montagnetol (S138) and erythrin (S139) were also isolated from Streptomyces sp. (LA3L2) that is the first reported actinomycete to produce these lichen-related compounds. In addition, chromomycin A2 (S140), chromomycin A3 (S141), and chromomycin 02-3D (S142) were reported to be separated from Streptomyces sp. (LA3L1) [Isolation of a new cytotoxic metabolite (287)  characte (LA3L1) .290), B (291), and C (292), together with two known analogs X-14881 A (288) and X-14881 B (289)   , were pr B (293)  was alsoy modest ,121.Streptomyces sp. strain T03 derived from the sponge Tethya sp. led to the identification of butenolide (294) (trypanosoma activity against Trypanosoma brucei brucei (IC50 = 31.77 μM) [295) (Actinomadura sp associated with a sea squirt Ecteinascidia turbinate. It showed potent activity against Clostridium difficile NAP1/B1/027 [de 294) , which e4 , which1.77 μM) . EcteinaM) [295)  was obta1/B1/027 ,115.S143) and two known compounds S144 and S145 were isolated from Streptomyces microflavus strain No. HVG29 is associated with the marine sponge Hymeniacidon perlevis collected from the coast of Dalian (China). Compounds S143–S145 were the first time to isolate deoxyuridine structures from S. microflavus associated with sponges [New nucleoside derivative ( sponges .Streptomyces sp. NIO 10068 derived from a marine sponge produced cinnamic acid (296)  , which wnt study .297, 298) (S146) from Solwaraspora sp. WMMB329 is associated with ascidian Trididemnum orbiculatum. The two novel compounds demonstrated antibacterial activity against MRSA and MSSA [In 2014, Ellis et al. reported isolation and identification of two novel trialkyl-substituted aromatic acids, solwaric acids A and B  , togetheand MSSA ,162.299, S147–S149) and diphosphatidylglycerol (S150) were produced by Microbacterium sp. HP2 associated with sponge Halichondria panacea collected at the Adriatic coast, Rovinj, Croatia. The major compound 299  was reported in 2017 from Streptomyces griseorubens sp. ASMR4 is associated with an unidentified soft coral collected in the Red Sea at the Hurghada coast, Egypt. Additionally, along with metabolite S144, seven other known metabolites S152–S158 were also discovered from the strain ASMR4 [Isolation of a new oxaphenalene derivative (in ASMR4 .S159) and tryptophan (S160) were produced by Rhodococcus sp. UA13 [S161) and 1,4-dihydroxy-2-naphthoic acid (S162) were isolated from the axenic culture of Saccharomonospora sp. UR22 [S160) and L-phenylalanine (S163) were produced by the sponge-associated Streptomyces sp. G246 [300  was produced by the sea anemone-derived Streptomyces sp. ZZ406 [Phenylacetic acid methyl ester (sp. UA13 . Two knosp. UR22 . In addisp. G246 . The kno246 [300  isolatedactivity . GTRI-02p. ZZ406 .S165) and thymidine-3-thioamine (S166) from sponge-associated Streptomyces sp. Call-36 [302)  transcriptional activation effect [In 2019, Shaala et al. reported the discovery of two new nucleosides thymidine-3-mercaptocarbamic acid   was prodE,8Z)/-5-oxo-6,8-tetradecadienoic acids   and the fish pathogen Tenacibaculum maritimum (preferred 304). In addition, compounds 303 and 304 displayed agonistic activity against peroxisome proliferator-activated receptors (PPARs) with an isoform specificity towards PPARα and PPARγ [A pair of geometrically isomeric unsaturated keto fatty acids   were idend PPARγ .305) (S167), actinopolysporin B (S168), and acanthosterol G (S169) was reported in 2021 from sponge-associated Streptomyces sp. RM66. Peroxidessethyl plakortide Z was active against solid tumor and L-1210 leukemia cell lines in vitro [Isolation of four metabolites ethyl plakortide Z (305) , seco-plin vitro .306, 109) were produced by an unidentified actinomycete strain CNC-837 obtained from the surface of the Caribbean brown alga Lobophora variegate. The new compounds, distantly related to antibiotics of the kijanimicin class, are potent inhibitors of topical PMA-induced edema in the mouse ear assay when administered either topically or IP [Two new anti-inflammatory compounds lobophorins A  and B  from the central Cantabrian Sea. Streptomyces cyaneofuscatus M-27 produced several antitumor antibiotics of the anthracycline family, of which two antibiotics were identified as daunomycin (307) and cosmomycin B (308) (309) (310)  . And it 8) (309) . In addi9) (310)  was sepaoperties .311)   was repoes Tü 57 .312) (S170) were separated from the seaweed-associated Streptomyces sp. HZP-2216E obtained from sea lettuce Ulva pertusa, a traditional Chinese medicine. They are both existing as zwitterion and streptopertusacin A showed moderate activity against the growth of MRSA [A unique indolizinium alkaloid streptopertusacin A (312)  and a no312) S were sep of MRSA .S171–S173), together with the known benzamides 2-acetamido-3-hydroxybenzamide (S174), 2-amino-3-hydroxybenzamide (S175), and 2-aminobenzamide (S176), were isolated from the Streptomyces sp. ZZ502 is associated with the seaweed Ulva conglobatea collected in the East China Sea [Three new compounds (hina Sea .S177 was reported in 2013 from Streptomyces cavourensis YY01-17 separated from the lichens grown in the Antarctic area [Isolation of a novel metabolite tic area .313 (S178–S180) from Streptomyces sundarbansensis strain WR1L1S8 associated with brown algae Fucus sp. collected in Bejaia coastline, Algeria. Compound 313 stood out as the most active of the series, showing a selective antibacterial activity against MRSA with a MIC of 6 μΜ [Polyketide 313  [2-hydro of 6 μΜ .314) and B (315)  produced by Streptomyces cyaneofuscatus M-27 associated with Fucus spiralis was first isolated from Streptomyces or marine environments [Germicidins A ( B (315) , discoveronments .316)  , a 28-me0−5µg/mL .317), together with bafilomycin D(320), 9-hydroxybafilomycin D (321), and bafilomycin A1(322)  and 21,22-en-9-hydroxybafilomycin D (319) (S182) were separated. Compounds 318 and 319 had potent activity against the proliferation of glioma U251 and C6 cells with IC50 values of 0.12–1.08 μM. In addition, they were active against MRSA with MIC values of 12.5 mg/mL. The four bafilomycins of compounds 320–322 and 317 showed potent activity in suppressing the proliferation of the four tested glioma cell lines with IC50 values of 0.35 to 2.95 µM. In addition, compounds 320–322 were reported to have antibacterial, antifungal, insecticidal, and herbicidal activities. Bafilomycins D and A1  also exhibited potent activity in inhibiting vacuolar-type ATPase [A new compound of 23-O-butyrylbafilomycin D( A1(322) , was iso D (319) , togethee ATPase ,171.323)  and colon carcinoma (DLD-1), but not normal mammary fibroblasts [Desertomycin G (323)  was separoblasts .S183, S184) and Germicidins K, L , together with six previously reported metabolites wailupemycin D (S187), wailupemycin E (S188), enterocin/vulgamycin (324), 5-deoxy-enterocin (325), germicidin A (314) and germicidin B (315)  , was rep griseus .326–328)   was repoor cells .329)   from Strectively .330) and imDKP (331) (Streptomyces praecox strain 291-11 separated from the rhizosphere of Undaria pinnatifida. The two compounds inhibited zoospores with a therapeutic ratio (LC50/EC50) of 17.7 and 21 and inhibited diatoms with a therapeutic ratio of 17.7 and 21, respectively [Two antifouling diketopiperazines bmDKP (KP (331)  were isoectively .S189) and cholest-4-en-3-one (S190) were discovered from Streptomyces sp. FX-58 is associated with marine plant Salicornia herbacea [332–335)   produced.2 μg/mL .336) and 2-hepta-1,5-dienyl-3,6-dihydroxy-5-(3-methylbut-2-enyl) benzaldehyde (337)  benzaldehyde (de (337)  were repus iniae .S191) in 2013 together with a known compound (S192) from lichen-derived Streptomyces cavourensis YY01-17 [338) , hydrocinnamic acid (S193), and (E)-cinnamic acid(S194) were separated from Streptomyces ambofaciens BI0048 associated with red alga Laurencia glandulifera [Shan-Shan Su et al. reported the discovery of a novel compound ( YY01-17 . And a n17 [338)  was prodbacteria . Three kdulifera .S195), the compound responsible for the “earth smell” and beta-patchoulene (S196) used as a fragrance agent in the perfume industry, were two major metabolites of Streptomyces carnosus M-40 [339) and Linoleic acid (340)  , which wes Tü 57 .Streptomyces (68%), Micromonospora (6%), and Nocardiopsis (3%) are the dominant producers , polyketides (33%), and peptides (15%) comprise the largest proportion of secondary metabolites, while roducers . Figure roducers .Approximately 64% of the SMs displayed various biological activities, especially antimicrobial activity and cytotoxicity . Interes9) is the earliest rifamycin antibiotic used in clinical application. Tetrodotoxin (105) has been widely used as an analgesic, sedative, antispasmodic, and local anesthetic in clinics. And daunomycin (307) has a good effect on acute myeloid leukemia. In addition, for these drugs already in clinical use, more clinical trials are underway for new diseases or new usages. .Molecules with excellent activities, which have been in clinical applications or have entered clinical trials, were listed in Metabolites from actinomycetes associated with marine organisms have proven to be an abundant source for the isolation of multiple potent bioactive metabolites with diverse structures. In this review, we attempt to discuss the significance of the special ecological status and genetic factors of these actinomycetes with multiple hosts. The chemical ecology underlying hosts–actinomycetes interactions provide a great opportunity for the discovery of novel drugs. During the co-evolution, these actinomycetes and their specific hosts constructed a coordinated and relatively independent micro-ecological environment, in which SMs can be tolerated by the host and are the active inhibiting specific external invasion. Therefore, actinomycetes associated with various marine hosts play an important ecological role in producing novel medicinal active compounds. Currently, there are relatively few studies on these actinomycetes, but many secondary metabolites have been isolated with excellent bioactivities. Some of these metabolites have been used in clinical applications or have entered clinical trials where they are expected to become new drugs. There is no doubt that further exploration can be a useful strategy for discovering novel marine natural products. These actinomycetes, however, are difficult to be cultured under experimental conditions. Therefore, in-depth exploration of the ecology of these actinomycetes to continuously optimize culture conditions is crucial for further research. Meanwhile, the use of advanced bioinformatics technology for gene detection of uncultured actinomycetes and heterologous expression of the collected biosynthetic gene clusters will be another important pathway for research on SMs of marine organism-associated actinomycetes.