{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:22Z","timestamp":1786121362603,"version":"build-2736575974"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Conventional antibiotics against slow-growing, mycolic acid-rich\n                      <jats:italic>Nocardia<\/jats:italic>\n                      often require prolonged therapy and are associated with high relapse rates. Membrane-targeting essential fatty acids may circumvent growth-dependent resistance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Five essential fatty acids were screened against 82 clinical\n                      <jats:italic>Nocardia<\/jats:italic>\n                      isolates by broth microdilution. Docosahexaenoic acid (DHA) was further assessed for bactericidal kinetics, membrane integrity by propidium iodide staining and scanning electron microscopy, transcriptomic profiling, and combined activity with amikacin and tobramycin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      \u03b1-Linolenic acid, \u03b3-linolenic acid, eicosapentaenoic acid and DHA exhibited comparable activity (MIC\n                      <jats:sub>50\/<\/jats:sub>\n                      MIC\n                      <jats:sub>90<\/jats:sub>\n                      : 31.25\/62.50 \u03bcM), corresponding to mass concentration ranges of 8.7 to 10.3 \u03bcg\/mL for MIC\n                      <jats:sub>50<\/jats:sub>\n                      and 17.4 to 20.6 \u03bcg\/mL for MIC\n                      <jats:sub>90<\/jats:sub>\n                      . However, arachidonic acid was markedly less active. DHA rapidly disrupted the\n                      <jats:italic>Nocardia<\/jats:italic>\n                      cell envelope, causing propidium iodide influx and ultrastructural damage, and achieved concentration-dependent bactericidal killing within 1 h, a feat not observed with imipenem. Transcriptomic analysis of the surviving subpopulation revealed downregulation of the proton-pumping Nuo complex, upregulation of type II NADH dehydrogenase (Ndh), and global induction of translation machinery. These transcriptional changes, together with pre-existing membrane damage, additively enhanced the activity of amikacin against intrinsically resistant\n                      <jats:italic>N. wallacei<\/jats:italic>\n                      (FICI, 0.51-0.56).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings demonstrate that DHA displays rapid membrane-disruptive activity and can enhance amikacin activity against\n                      <jats:italic>Nocardia<\/jats:italic>\n                      under the defined\n                      <jats:italic>in vitro<\/jats:italic>\n                      conditions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1878912","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:21:53Z","timestamp":1786076513000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Essential fatty acids disrupt the mycolic acid-rich cell envelope of clinical Nocardia isolates: a membrane-targeting approach to combat persistent infections"],"prefix":"10.3389","volume":"16","author":[{"given":"Ming","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwang","family":"Xie","sequence":"additional","affiliation":[{"name":"CAS Center for Excellence in Nanoscience, Beijing Key Laboratory of Micro-Nano Energy and Sensor, Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianmeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Aerospace Center Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Luo","sequence":"additional","affiliation":[{"name":"CAS Center for Excellence in Nanoscience, Beijing Key Laboratory of Micro-Nano Energy and Sensor, Beijing Institute of Nanoenergy and Nanosystems, Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/s41579-025-01155-0","article-title":"The role of bacterial metabolism in antimicrobial resistance","volume":"23","author":"Ahmad","year":"2025","journal-title":"Nat. Rev. Microbiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12941-022-00511-9","article-title":"A fatal case of disseminated nocardiosis due to Nocardia otitidiscaviarum resistant to trimethoprim-sulfamethoxazole: case report and literature review","volume":"21","author":"Barry","year":"2022","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1038\/s41564-025-02133-1","article-title":"Polymyxin B lethality requires energy-dependent outer membrane disruption","volume":"10","author":"Borrelli","year":"2025","journal-title":"Nat. Microbiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1016\/j.cell.2014.11.017","article-title":"Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery","volume":"159","author":"Cho","year":"2014","journal-title":"Cell"},{"key":"B5","article-title":"Susceptibility testing of Mycobacteria, Nocardiae, and other Aerobic Actinomycetes; approved standard-second edition","volume-title":"CLSI Document M24-A2","year":"2011"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2000535","DOI":"10.1183\/13993003.00535-2020","article-title":"Treatment of nontuberculous mycobacterial pulmonary disease: An official ATS\/ERS\/ESCMID\/IDSA clinical practice guideline","volume":"56","author":"Daley","year":"2020","journal-title":"Eur. Respir. J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"42090","DOI":"10.1038\/s41598-025-26244-1","article-title":"The global epidemiology, risk factors, and mortality prediction of nocardiosis: An easily missed opportunistic infection","volume":"15","author":"Du","year":"2025","journal-title":"Sci. Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nrmicro.2017.42","article-title":"Persistent bacterial infections and persister cells","volume":"15","author":"Fisher","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/foods14030473","article-title":"Lipids in clinical nutrition and health: narrative review and dietary recommendations","volume":"14","author":"Frydrych","year":"2025","journal-title":"Foods"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/mmbr.00037-22","article-title":"Antimicrobial peptides and small molecules targeting the cell membrane of Staphylococcus aureus","volume":"87","author":"Ganesan","year":"2023","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1111\/j.1574-6968.1984.tb01065.x","article-title":"Propionyl-CoA carboxylase in Nocardia mediterranei","volume":"23","author":"Gygax","year":"1984","journal-title":"FEMS Microbiol. Lett."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2306","DOI":"10.1093\/jac\/dkad236","article-title":"Phenotypic and genotypic analysis of antimicrobial resistance in Nocardia species","volume":"78","author":"Hershko","year":"2023","journal-title":"J. Antimicrob. Chemother."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2024.107089","article-title":"WarA, a remote homolog of NpmA and KamB from Nocardia wallacei, confers broad spectrum aminoglycoside resistance in Nocardia and Mycobacteria","volume":"63","author":"Hershko","year":"2024","journal-title":"Int. J. Antimicrob. Agents"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1503\/cmaj.111152","article-title":"Considerations when prescribing trimethoprim-sulfamethoxazole","volume":"183","author":"Ho","year":"2011","journal-title":"Cmaj"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1128\/aac.01352-06","article-title":"Daptomycin susceptibility of unusual gram-positive bacteria: Comparison of results obtained by the Etest and the broth microdilution method","volume":"51","author":"Huang","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"B16","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/nrmicro2474","article-title":"Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections","volume":"9","author":"Hurdle","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1016\/j.micinf.2008.08.004","article-title":"Effects of omega-3 and -6 fatty acids on Mycobacterium tuberculosis in macrophages and in mice","volume":"10","author":"Jordao","year":"2008","journal-title":"Microbes Infect."},{"key":"B18","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1007\/s002030050631","article-title":"Propionyl-CoA carboxylase of Myxococcus xanthus: Catalytic properties and function in developing cells","volume":"170","author":"Kimura","year":"1998","journal-title":"Arch. Microbiol."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2025.107629","article-title":"Antibiofilm activity of arachidonic acid against linezolid-resistant Enterococcus faecalis: A potential strategy for combating biofilm-related infections","volume":"205","author":"Li","year":"2025","journal-title":"Microb. Pathog."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4534","DOI":"10.1128\/jcm.01073-10","article-title":"Antimicrobial susceptibility testing and profiling of Nocardia species and other aerobic actinomycetes from South Africa: Comparative evaluation of broth microdilution versus the Etest","volume":"48","author":"Lowman","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.chembiol.2013.11.011","article-title":"Mycolic acids: Structures, biosynthesis, and beyond","volume":"21","author":"Marrakchi","year":"2014","journal-title":"Chem. Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3131","DOI":"10.1016\/j.bbamem.2016.10.002","article-title":"Eicosapentaenoic acid reduces membrane fluidity, inhibits cholesterol domain formation, and normalizes bilayer width in atherosclerotic-like model membranes","volume":"1858","author":"Mason","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00364-18","article-title":"Pathogenic Nocardia cyriacigeorgica and Nocardia nova evolve to resist trimethoprim-sulfamethoxazole by both expected and unexpected pathways","volume":"62","author":"Mehta","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"5814","DOI":"10.1021\/acs.jpcb.9b04326","article-title":"Branched-chain fatty acid content modulates structure, fluidity, and phase in model microbial cell membranes","volume":"123","author":"Mostofian","year":"2019","journal-title":"J. Phys. Chem. B"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02281-21","article-title":"Synergism versus additivity: Defining the interactions between common disinfectants","volume":"12","author":"Noel","year":"2021","journal-title":"mBio"},{"key":"B26","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1128\/cmr.00064-16","article-title":"Polymyxins: Antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes","volume":"30","author":"Poirel","year":"2017","journal-title":"Clin. Microbiol. Rev."},{"key":"B27","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1038\/s41579-022-00700-5","article-title":"The physiology and genetics of bacterial responses to antibiotic combinations","volume":"20","author":"Roemhild","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"214","DOI":"10.3855\/jidc.10169","article-title":"Fatal pulmonary infection by trimethoprim-sulfamethoxazole resistant Nocardia otitidiscaviarum: Report of two cases and review","volume":"14","author":"Saksena","year":"2020","journal-title":"J. Infect. Dev. Ctries."},{"key":"B29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1164\/rccm.202410-2096ST","article-title":"Updates on the treatment of drug-susceptible and drug-resistant tuberculosis: An official ATS\/CDC\/ERS\/IDSA clinical practice guideline","volume":"211","author":"Saukkonen","year":"2025","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"4666","DOI":"10.1038\/s41467-023-40416-5","article-title":"Molecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome","volume":"14","author":"Seely","year":"2023","journal-title":"Nat. Commun."},{"key":"B31","doi-asserted-by":"publisher","first-page":"A16909","DOI":"10.1161\/circ.148.suppl_1.16909","article-title":"Abstract 16909: Eicosapentaenoic acid and docosahexaenoic acid have competing effects on membrane lipid dynamics due to differences in structure","volume":"148","author":"Sherratt","year":"2023","journal-title":"Circulation"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00027-21","article-title":"Updated review on Nocardia species: 2006-2021","volume":"35","author":"Traxler","year":"2022","journal-title":"Clin. Microbiol. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1073\/pnas.1721545115","article-title":"Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence","volume":"115","author":"Vilch\u00e8ze","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4181","DOI":"10.2147\/idr.s373991","article-title":"Antibiofilm activity of essential fatty acids against Candida albicans from vulvovaginal candidiasis and bloodstream infections","volume":"15","author":"Wang","year":"2022","journal-title":"Infect. Drug Resist."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1099\/ijsem.0.005601","article-title":"Nocardia sputi sp. nov. isolated from the sputum of patients with pulmonary infection","volume":"72","author":"Wang","year":"2022","journal-title":"Int. J. Syst. Evol. Microbiol."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1266674","article-title":"Antimicrobial and antibiofilm effects of essential fatty acids against clinically isolated vancomycin-resistant Enterococcus faecium","volume":"13","author":"Wei","year":"2023","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1186\/s12866-021-02412-x","article-title":"MLSA phylogeny and antimicrobial susceptibility of clinical Nocardia isolates: A multicenter retrospective study in China","volume":"21","author":"Wei","year":"2021","journal-title":"BMC Microbiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e53","DOI":"10.1093\/cid\/ciae643","article-title":"State-of-the-art review: Modern approach to nocardiosis-diagnosis, management, and uncertainties","volume":"80","author":"Yetmar","year":"2025","journal-title":"Clin. Infect. Dis."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19041114","article-title":"Antibacterial free fatty acids and monoglycerides: Biological activities, experimental testing, and therapeutic applications","volume":"19","author":"Yoon","year":"2018","journal-title":"Int. J. Mol. Sci."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1878912\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:21:55Z","timestamp":1786076515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2026.1878912\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":39,"alternative-id":["10.3389\/fcimb.2026.1878912"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2026.1878912","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]},"article-number":"1878912"}}