{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T11:55:50Z","timestamp":1792410950146,"version":"4.4.0"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["PATH"],"award-info":[{"award-number":["PATH"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["PATH"],"award-info":[{"award-number":["PATH"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI173004"],"award-info":[{"award-number":["R01AI173004"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI179695"],"award-info":[{"award-number":["R01AI179695"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI167978"],"award-info":[{"award-number":["R01AI167978"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Microbiol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Intracellular bacterial reservoirs contribute to antibiotic treatment failure by fostering metabolically dormant persister cells that are highly tolerant to killing. However, strategies to effectively target intracellular persister cells remain limited. Here we developed a high-throughput screen to identify compounds that modulate the metabolic activity of intracellular\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    . The identified compound, KL1, increases intracellular bacterial metabolic activity and sensitizes persister populations of\n                    <jats:italic>S. aureus<\/jats:italic>\n                    to antibiotics, without causing cytotoxicity or bacterial outgrowth. KL1 also exhibits adjuvant activity against intramacrophage\n                    <jats:italic>Salmonella enterica<\/jats:italic>\n                    Typhimurium and\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    , as well as in murine infection models of\n                    <jats:italic>S. aureus<\/jats:italic>\n                    and\n                    <jats:italic>S<\/jats:italic>\n                    . Typhimurium infection. Transcriptomic analysis and further mechanistic studies reveal that KL1 modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating a key inducer of antibiotic tolerance. Our findings highlight the potential to target intracellular persisters by stimulating their metabolism. There are two major problems in the field of antimicrobial chemotherapy\u2013antibiotic resistance and antibiotic tolerance. Antibiotic tolerance has been frequently connected with poor treatment outcomes in the clinic. Unlike antibiotic resistance, which permits bacterial growth in the presence of drugs, antibiotic tolerance allows bacteria to withstand multiple antibiotics for prolonged periods. The extended survival of tolerant bacteria further predisposes them to evolve antibiotic resistance over time, underscoring the critical need to address antibiotic tolerance. Host interactions have been shown to induce persister formation in numerous pathogens, with the production of reactive oxygen and nitrogen species heavily implicated in the collapse of bacterial metabolic activity and entry into an antibiotic-tolerant state. Yet, tools to study or target this process remain limited. Here we developed a high-throughput screen to identify compounds that modulate intracellular\n                    <jats:italic>S. aureus<\/jats:italic>\n                    metabolism, leading to the discovery of KL1, a host-directed compound that sensitizes persisters to antibiotic killing.\n                  <\/jats:p>","DOI":"10.1038\/s41564-025-02124-2","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T09:03:51Z","timestamp":1760087031000},"page":"3013-3025","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["A host-directed adjuvant sensitizes intracellular bacterial persisters to antibiotics"],"prefix":"10.1038","volume":"10","author":[{"given":"Kuan-Yi","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6538-4012","authenticated-orcid":false,"given":"Matthew J. G.","family":"Eldridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfeng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2790-0300","authenticated-orcid":false,"given":"Rachel T.","family":"Giorgio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin I.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4872-3107","authenticated-orcid":false,"given":"Nikki J.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Hardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Axtman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8955-359X","authenticated-orcid":false,"given":"Sarah E.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Vance G.","family":"Fowler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2284-5050","authenticated-orcid":false,"given":"Qingyun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9877-4180","authenticated-orcid":false,"given":"Sophie","family":"Helaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8138-5421","authenticated-orcid":false,"given":"Kenneth H.","family":"Pearce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2155-8375","authenticated-orcid":false,"given":"Brian P.","family":"Conlon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"2124_CR1","doi-asserted-by":"crossref","unstructured":"Conlon, B. P. et al. Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat. Microbiol. 1, 16051 (2016).","DOI":"10.1038\/nmicrobiol.2016.51"},{"key":"2124_CR2","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nrmicro.2017.42","volume":"15","author":"RA Fisher","year":"2017","unstructured":"Fisher, R. A., Gollan, B. & Helaine, S. Persistent bacterial infections and persister cells. Nat. Rev. Microbiol. 15, 453\u2013464 (2017).","journal-title":"Nat. Rev. Microbiol."},{"key":"2124_CR3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41564-020-00819-2","volume":"6","author":"ML Pinel-Marie","year":"2021","unstructured":"Pinel-Marie, M. L. et al. RNA antitoxin SprF1 binds ribosomes to attenuate translation and promote persister cell formation in Staphylococcus aureus. Nat. Microbiol. 6, 209\u2013220 (2021).","journal-title":"Nat. Microbiol."},{"key":"2124_CR4","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-024-51144-9","volume":"15","author":"JA Freiberg","year":"2024","unstructured":"Freiberg, J. A. et al. Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus. Nat. Commun. 15, 6734 (2024).","journal-title":"Nat. Commun."},{"key":"2124_CR5","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1128\/AAC.02135-12","volume":"57","author":"BW Kwan","year":"2013","unstructured":"Kwan, B. W., Valenta, J. A., Benedik, M. J. & Wood, T. K. Arrested protein synthesis increases persister-like cell formation. Antimicrob. Agents Chemother. 57, 1468\u20131473 (2013).","journal-title":"Antimicrob. Agents Chemother."},{"key":"2124_CR6","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1111\/1462-2920.14828","volume":"22","author":"S Song","year":"2020","unstructured":"Song, S. & Wood, T. K. Persister cells resuscitate via ribosome modification by 23S rRNA pseudouridine synthase RluD. Environ. Microbiol. 22, 850\u2013857 (2020).","journal-title":"Environ. Microbiol."},{"key":"2124_CR7","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41564-019-0627-y","volume":"5","author":"SE Rowe","year":"2020","unstructured":"Rowe, S. E. et al. Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection. Nat. Microbiol. 5, 282\u2013290 (2020).","journal-title":"Nat. Microbiol."},{"key":"2124_CR8","volume":"89","author":"JE Beam","year":"2021","unstructured":"Beam, J. E. et al. Macrophage-produced peroxynitrite induces antibiotic tolerance and supersedes intrinsic mechanisms of persister formation. Infect. Immun. 89, e0028621 (2021).","journal-title":"Infect. Immun."},{"key":"2124_CR9","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-15966-7","volume":"11","author":"F Peyrusson","year":"2020","unstructured":"Peyrusson, F. et al. Intracellular Staphylococcus aureus persisters upon antibiotic exposure. Nat. Commun. 11, 2200 (2020).","journal-title":"Nat. Commun."},{"key":"2124_CR10","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1126\/science.1244705","volume":"343","author":"S Helaine","year":"2014","unstructured":"Helaine, S. et al. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343, 204\u2013208 (2014).","journal-title":"Science"},{"key":"2124_CR11","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1084\/jem.20151248","volume":"213","author":"Y Liu","year":"2016","unstructured":"Liu, Y. et al. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J. Exp. Med. 213, 809\u2013825 (2016).","journal-title":"J. Exp. Med."},{"key":"2124_CR12","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.chom.2024.04.019","volume":"32","author":"S Helaine","year":"2024","unstructured":"Helaine, S., Conlon, B. P., Davis, K. M. & Russell, D. G. Host stress drives tolerance and persistence: the bane of anti-microbial therapeutics. Cell Host Microbe 32, 852\u2013862 (2024).","journal-title":"Cell Host Microbe"},{"key":"2124_CR13","doi-asserted-by":"crossref","DOI":"10.1128\/spectrum.02313-21","volume":"10","author":"F Peyrusson","year":"2022","unstructured":"Peyrusson, F., Nguyen, T. K., Najdovski, T. & Van Bambeke, F. Host cell oxidative stress induces dormant Staphylococcus aureus persisters. Microbiol. Spectr. 10, e0231321 (2022).","journal-title":"Microbiol. Spectr."},{"key":"2124_CR14","doi-asserted-by":"crossref","unstructured":"Raneses, J. R., Ellison, A. L., Liu, B. & Davis, K. M. Subpopulations of stressed Yersinia pseudotuberculosis preferentially survive doxycycline treatment within host tissues. mBio 11, e00901-20 (2020).","DOI":"10.1128\/mBio.00901-20"},{"key":"2124_CR15","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1016\/j.chom.2021.10.002","volume":"29","author":"PWS Hill","year":"2021","unstructured":"Hill, P. W. S. et al. The vulnerable versatility of Salmonella antibiotic persisters during infection. Cell Host Microbe 29, 1757\u20131773.e10 (2021).","journal-title":"Cell Host Microbe"},{"key":"2124_CR16","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/j.1751-7915.2011.00327.x","volume":"5","author":"SH Hong","year":"2012","unstructured":"Hong, S. H., Wang, X., O\u2019Connor, H. F., Benedik, M. J. & Wood, T. K. Bacterial persistence increases as environmental fitness decreases. Microb. Biotechnol. 5, 509\u2013522 (2012).","journal-title":"Microb. Biotechnol."},{"key":"2124_CR17","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1084\/jem.20160334","volume":"213","author":"BG Surewaard","year":"2016","unstructured":"Surewaard, B. G. et al. Identification and treatment of the Staphylococcus aureus reservoir in vivo. J. Exp. Med. 213, 1141\u20131151 (2016).","journal-title":"J. Exp. Med."},{"key":"2124_CR18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.tim.2008.11.004","volume":"17","author":"P Sendi","year":"2009","unstructured":"Sendi, P. & Proctor, R. A. Staphylococcus aureus as an intracellular pathogen: the role of small colony variants. Trends Microbiol. 17, 54\u201358 (2009).","journal-title":"Trends Microbiol."},{"key":"2124_CR19","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1086\/432735","volume":"192","author":"S Clement","year":"2005","unstructured":"Clement, S. et al. Evidence of an intracellular reservoir in the nasal mucosa of patients with recurrent Staphylococcus aureus rhinosinusitis. J. Infect. Dis. 192, 1023\u20131028 (2005).","journal-title":"J. Infect. Dis."},{"key":"2124_CR20","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/cmi.12527","volume":"18","author":"RS Flannagan","year":"2016","unstructured":"Flannagan, R. S., Heit, B. & Heinrichs, D. E. Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination. Cell. Microbiol. 18, 514\u2013535 (2016).","journal-title":"Cell. Microbiol."},{"key":"2124_CR21","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.tim.2008.11.005","volume":"17","author":"C Garzoni","year":"2009","unstructured":"Garzoni, C. & Kelley, W. L. Staphylococcus aureus: new evidence for intracellular persistence. Trends Microbiol. 17, 59\u201365 (2009).","journal-title":"Trends Microbiol."},{"key":"2124_CR22","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1093\/jac\/dkz559","volume":"75","author":"R Kuehl","year":"2020","unstructured":"Kuehl, R., Morata, L., Meylan, S., Mensa, J. & Soriano, A. When antibiotics fail: a clinical and microbiological perspective on antibiotic tolerance and persistence of Staphylococcus aureus. J. Antimicrob. Chemother. 75, 1071\u20131086 (2020).","journal-title":"J. Antimicrob. Chemother."},{"key":"2124_CR23","doi-asserted-by":"crossref","unstructured":"Nandhini, P. et al. Recent developments in methicillin-resistant Staphylococcus aureus (MRSA) treatment: a review. Antibiotics 11, 606 (2022).","DOI":"10.3390\/antibiotics11050606"},{"key":"2124_CR24","volume":"11","author":"KY Lu","year":"2023","unstructured":"Lu, K. Y. et al. Antibiotic tolerance and treatment outcomes in cystic fibrosis methicillin-resistant Staphylococcus aureus infections. Microbiol. Spectr. 11, e0406122 (2023).","journal-title":"Microbiol. Spectr."},{"key":"2124_CR25","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-24127-3","volume":"12","author":"P Santucci","year":"2021","unstructured":"Santucci, P. et al. Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide. Nat. Commun. 12, 3816 (2021).","journal-title":"Nat. Commun."},{"key":"2124_CR26","doi-asserted-by":"crossref","first-page":"e1012033","DOI":"10.1371\/journal.ppat.1012033","volume":"20","author":"S Ronneau","year":"2024","unstructured":"Ronneau, S., Michaux, C., Giorgio, R. T. & Helaine, S. Intoxication of antibiotic persisters by host RNS inactivates their efflux machinery during infection. PLoS Pathog. 20, e1012033 (2024).","journal-title":"PLoS Pathog."},{"key":"2124_CR27","doi-asserted-by":"crossref","first-page":"e1012144","DOI":"10.1371\/journal.ppat.1012144","volume":"20","author":"P Hovhannisyan","year":"2024","unstructured":"Hovhannisyan, P. et al. Infection of human organoids supports an intestinal niche for Chlamydia trachomatis. PLoS Pathog. 20, e1012144 (2024).","journal-title":"PLoS Pathog."},{"key":"2124_CR28","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.chom.2017.10.006","volume":"22","author":"H Liu","year":"2017","unstructured":"Liu, H. et al. Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-mediated T cell responses. Cell Host Microbe 22, 653\u2013666 e655 (2017).","journal-title":"Cell Host Microbe"},{"key":"2124_CR29","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.jbiotec.2011.12.009","volume":"157","author":"S Sunya","year":"2012","unstructured":"Sunya, S., Gorret, N., Delvigne, F., Uribelarrea, J. L. & Molina-Jouve, C. Real-time monitoring of metabolic shift and transcriptional induction of yciG::luxCDABE E. coli reporter strain to a glucose pulse of different concentrations. J. Biotechnol. 157, 379\u2013390 (2012).","journal-title":"J. Biotechnol."},{"key":"2124_CR30","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1128\/AEM.65.2.813-821.1999","volume":"65","author":"A Unge","year":"1999","unstructured":"Unge, A., Tombolini, R., Molbak, L. & Jansson, J. K. Simultaneous monitoring of cell number and metabolic activity of specific bacterial populations with a dual gfp-luxAB marker system. Appl. Environ. Microbiol. 65, 813\u2013821 (1999).","journal-title":"Appl. Environ. Microbiol."},{"key":"2124_CR31","doi-asserted-by":"crossref","first-page":"4920","DOI":"10.1128\/aem.63.12.4920-4928.1997","volume":"63","author":"L Kragelund","year":"1997","unstructured":"Kragelund, L., Hosbond, C. & Nybroe, O. Distribution of metabolic activity and phosphate starvation response of lux-tagged Pseudomonas fluorescens reporter bacteria in the barley rhizosphere. Appl. Environ. Microbiol. 63, 4920\u20134928 (1997).","journal-title":"Appl. Environ. Microbiol."},{"key":"2124_CR32","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.csbj.2018.11.003","volume":"16","author":"E Brodl","year":"2018","unstructured":"Brodl, E., Winkler, A. & Macheroux, P. Molecular mechanisms of bacterial bioluminescence. Comput. Struct. Biotechnol. J. 16, 551\u2013564 (2018).","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"2124_CR33","volume":"10","author":"JJ Lee","year":"2019","unstructured":"Lee, J. J. et al. Transient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis. Nat. Commun. 10, 2928 (2019).","journal-title":"Nat. Commun."},{"key":"2124_CR34","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.chom.2023.05.002","volume":"31","author":"S Ronneau","year":"2023","unstructured":"Ronneau, S., Michaux, C. & Helaine, S. Decline in nitrosative stress drives antibiotic persister regrowth during infection. Cell Host Microbe 31, 993\u20131006.e6 (2023).","journal-title":"Cell Host Microbe"},{"key":"2124_CR35","doi-asserted-by":"crossref","unstructured":"Thurlow, L. R., Stephens, A. C., Hurley, K. E. & Richardson, A. R. Lack of nutritional immunity in diabetic skin infections promotes Staphylococcus aureus virulence. Sci. Adv. 6, eabc5569 (2020).","DOI":"10.1126\/sciadv.abc5569"},{"key":"2124_CR36","doi-asserted-by":"crossref","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","volume":"51","author":"The UniProt Consortium.","year":"2023","unstructured":"The UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 51, D523\u2013D531 (2023).","journal-title":"Nucleic Acids Res."},{"key":"2124_CR37","doi-asserted-by":"crossref","first-page":"D20","DOI":"10.1093\/nar\/gkab1112","volume":"50","author":"EW Sayers","year":"2022","unstructured":"Sayers, E. W. et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 50, D20\u2013D26 (2022).","journal-title":"Nucleic Acids Res."},{"key":"2124_CR38","doi-asserted-by":"crossref","DOI":"10.1128\/mmbr.00174-22","volume":"87","author":"KL Cotten","year":"2023","unstructured":"Cotten, K. L. & Davis, K. M. Bacterial heterogeneity and antibiotic persistence: bacterial mechanisms utilized in the host environment. Microbiol. Mol. Biol. Rev. 87, e0017422 (2023).","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"2124_CR39","unstructured":"National Center for Biotechnology Information. PubChem Compound Summary for CID 5361454. (PubChem, accessed 21 September 2025); https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/5361454"},{"key":"2124_CR40","doi-asserted-by":"crossref","first-page":"583","DOI":"10.21037\/atm-22-1884","volume":"10","author":"Y Li","year":"2022","unstructured":"Li, Y., Li, G., Zhang, L., Li, Y. & Zhao, Z. G9a promotes inflammation in Streptococcus pneumoniae induced pneumonia mice by stimulating M1 macrophage polarization and H3K9me2 methylation in FOXP1 promoter region. Ann. Transl. Med 10, 583 (2022).","journal-title":"Ann. Transl. Med"},{"key":"2124_CR41","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.chembiol.2023.09.012","volume":"30","author":"A Muneer","year":"2023","unstructured":"Muneer, A. et al. Non-canonical function of histone methyltransferase G9a in the translational regulation of chronic inflammation. Cell Chem. Biol. 30, 1525\u20131541 e1527 (2023).","journal-title":"Cell Chem. Biol."},{"key":"2124_CR42","doi-asserted-by":"crossref","DOI":"10.1016\/j.metabol.2020.154404","volume":"114","author":"X Wang","year":"2021","unstructured":"Wang, X. et al. Histone methyltransferases G9a mediated lipid-induced M1 macrophage polarization through negatively regulating CD36. Metabolism 114, 154404 (2021).","journal-title":"Metabolism"},{"key":"2124_CR43","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3389\/fimmu.2017.00429","volume":"8","author":"S Scheer","year":"2017","unstructured":"Scheer, S. & Zaph, C. The lysine methyltransferase G9a in immune cell differentiation and function. Front. Immunol. 8, 429 (2017).","journal-title":"Front. Immunol."},{"key":"2124_CR44","volume":"5","author":"C Liu","year":"2014","unstructured":"Liu, C. et al. A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing. Nat. Commun. 5, 5733 (2014).","journal-title":"Nat. Commun."},{"key":"2124_CR45","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.freeradbiomed.2016.08.033","volume":"101","author":"N Rios","year":"2016","unstructured":"Rios, N. et al. Sensitive detection and estimation of cell-derived peroxynitrite fluxes using fluorescein-boronate. Free Radic. Biol. Med. 101, 284\u2013295 (2016).","journal-title":"Free Radic. Biol. Med."},{"key":"2124_CR46","doi-asserted-by":"crossref","first-page":"e1008892","DOI":"10.1371\/journal.ppat.1008892","volume":"16","author":"LF Westblade","year":"2020","unstructured":"Westblade, L. F., Errington, J. & Dorr, T. Antibiotic tolerance. PLoS Pathog. 16, e1008892 (2020).","journal-title":"PLoS Pathog."},{"key":"2124_CR47","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/s41579-019-0196-3","volume":"17","author":"NQ Balaban","year":"2019","unstructured":"Balaban, N. Q. et al. Definitions and guidelines for research on antibiotic persistence. Nat. Rev. Microbiol. 17, 441\u2013448 (2019).","journal-title":"Nat. Rev. Microbiol."},{"key":"2124_CR48","doi-asserted-by":"crossref","unstructured":"Huemer, M. et al. Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success. Proc. Natl Acad. Sci. USA 118, e2014920118 (2021).","DOI":"10.1073\/pnas.2014920118"},{"key":"2124_CR49","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/s41564-018-0218-3","volume":"3","author":"ND Hicks","year":"2018","unstructured":"Hicks, N. D. et al. Clinically prevalent mutations in Mycobacterium tuberculosis alter propionate metabolism and mediate multidrug tolerance. Nat. Microbiol. 3, 1032\u20131042 (2018).","journal-title":"Nat. Microbiol."},{"key":"2124_CR50","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1093\/cid\/ciq146","volume":"52","author":"C Liu","year":"2011","unstructured":"Liu, C. et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin. Infect. Dis. 52, e18\u2013e55 (2011).","journal-title":"Clin. Infect. Dis."},{"key":"2124_CR51","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1016\/j.cmi.2022.03.015","volume":"28","author":"AD Bai","year":"2022","unstructured":"Bai, A. D. et al. Staphylococcus aureus bacteraemia mortality: a systematic review and meta-analysis. Clin. Microbiol. Infect. 28, 1076\u20131084 (2022).","journal-title":"Clin. Microbiol. Infect."},{"key":"2124_CR52","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1016\/j.drudis.2021.05.018","volume":"26","author":"J Tasse","year":"2021","unstructured":"Tasse, J., Dieppois, G., Peyrane, F. & Tesse, N. Improving the ability of antimicrobial susceptibility tests to predict clinical outcome accurately: adding metabolic evasion to the equation. Drug Discov. Today 26, 2182\u20132189 (2021).","journal-title":"Drug Discov. Today"},{"key":"2124_CR53","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41392-024-01866-5","volume":"9","author":"H Niu","year":"2024","unstructured":"Niu, H., Gu, J. & Zhang, Y. Bacterial persisters: molecular mechanisms and therapeutic development. Signal Transduct. Target. Ther. 9, 174 (2024).","journal-title":"Signal Transduct. Target. Ther."},{"key":"2124_CR54","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1146\/annurev-micro-020518-115650","volume":"73","author":"B Gollan","year":"2019","unstructured":"Gollan, B., Grabe, G., Michaux, C. & Helaine, S. Bacterial persisters and infection: past, present, and progressing. Annu. Rev. Microbiol. 73, 359\u2013385 (2019).","journal-title":"Annu. Rev. Microbiol."},{"key":"2124_CR55","doi-asserted-by":"crossref","unstructured":"Harms, A., Maisonneuve, E. & Gerdes, K. Mechanisms of bacterial persistence during stress and antibiotic exposure. Science 354, aaf4268 (2016).","DOI":"10.1126\/science.aaf4268"},{"key":"2124_CR56","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-08190-x","volume":"10","author":"MJ Ellis","year":"2019","unstructured":"Ellis, M. J. et al. A macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium. Nat. Commun. 10, 197 (2019).","journal-title":"Nat. Commun."},{"key":"2124_CR57","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1016\/j.chembiol.2020.08.015","volume":"27","author":"EJ Zheng","year":"2020","unstructured":"Zheng, E. J., Stokes, J. M. & Collins, J. J. Eradicating bacterial persisters with combinations of strongly and weakly metabolism-dependent antibiotics. Cell Chem. Biol. 27, 1544\u20131552.e3 (2020).","journal-title":"Cell Chem. Biol."},{"key":"2124_CR58","doi-asserted-by":"crossref","DOI":"10.1128\/iai.00339-23","volume":"92","author":"DD Rockey","year":"2024","unstructured":"Rockey, D. D., Wang, X., Debrine, A., Grieshaber, N. & Grieshaber, S. S. Metabolic dormancy in Chlamydia trachomatis treated with different antibiotics. Infect. Immun. 92, e0033923 (2024).","journal-title":"Infect. Immun."},{"key":"2124_CR59","doi-asserted-by":"crossref","first-page":"e00100-11","DOI":"10.1128\/mBio.00100-11","volume":"2","author":"I Keren","year":"2011","unstructured":"Keren, I., Minami, S., Rubin, E. & Lewis, K. Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. mBio 2, e00100-11 (2011).","journal-title":"mBio"},{"key":"2124_CR60","doi-asserted-by":"crossref","first-page":"e1009550","DOI":"10.1371\/journal.ppat.1009550","volume":"17","author":"CH Luk","year":"2021","unstructured":"Luk, C. H. et al. Salmonella enters a dormant state within human epithelial cells for persistent infection. PLoS Pathog. 17, e1009550 (2021).","journal-title":"PLoS Pathog."},{"key":"2124_CR61","volume":"10","author":"W Eisenreich","year":"2020","unstructured":"Eisenreich, W., Rudel, T., Heesemann, J. & Goebel, W. Persistence of intracellular bacterial pathogens\u2013with a focus on the metabolic perspective. Front. Cell. Infect. Microbiol. 10, 615450 (2020).","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"2124_CR62","doi-asserted-by":"crossref","first-page":"L941","DOI":"10.1152\/ajplung.00017.2002","volume":"282","author":"FC Fang","year":"2002","unstructured":"Fang, F. C. & Vazquez-Torres, A. Nitric oxide production by human macrophages: there\u2019s NO doubt about it. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L941\u2013L943 (2002).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2124_CR63","volume":"26","author":"JE Beam","year":"2023","unstructured":"Beam, J. E. et al. Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus. iScience 26, 107942 (2023).","journal-title":"iScience"},{"key":"2124_CR64","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/318667a0","volume":"318","author":"E Blasi","year":"1985","unstructured":"Blasi, E. et al. Selective immortalization of murine macrophages from fresh bone marrow by a raf\/myc recombinant murine retrovirus. Nature 318, 667\u2013670 (1985).","journal-title":"Nature"},{"key":"2124_CR65","doi-asserted-by":"crossref","first-page":"e0214088","DOI":"10.1371\/journal.pone.0214088","volume":"14","author":"S Borrell","year":"2019","unstructured":"Borrell, S. et al. Reference set of Mycobacterium tuberculosis clinical strains: a tool for research and product development. PLoS ONE 14, e0214088 (2019).","journal-title":"PLoS ONE"},{"key":"2124_CR66","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1038\/s41564-024-01697-8","volume":"9","author":"CV Mulholland","year":"2024","unstructured":"Mulholland, C. V. et al. Propionate prevents loss of the PDIM virulence lipid in Mycobacterium tuberculosis. Nat. Microbiol. 9, 1607\u20131618 (2024).","journal-title":"Nat. Microbiol."},{"key":"2124_CR67","doi-asserted-by":"crossref","first-page":"7851","DOI":"10.1128\/IAI.69.12.7851-7857.2001","volume":"69","author":"BT Bateman","year":"2001","unstructured":"Bateman, B. T., Donegan, N. P., Jarry, T. M., Palma, M. & Cheung, A. L. Evaluation of a tetracycline-inducible promoter in Staphylococcus aureus in vitro and in vivo and its application in demonstrating the role of sigB in microcolony formation. Infect. Immun. 69, 7851\u20137857 (2001).","journal-title":"Infect. Immun."},{"key":"2124_CR68","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/7651_2014_183","volume":"1373","author":"MR Grosser","year":"2016","unstructured":"Grosser, M. R. & Richardson, A. R. Method for preparation and electroporation of S. aureus and S. epidermidis. Methods Mol. Biol. 1373, 51\u201357 (2016).","journal-title":"Methods Mol. Biol."},{"key":"2124_CR69","volume":"7","author":"NW de Jong","year":"2017","unstructured":"de Jong, N. W., van der Horst, T., van Strijp, J. A. & Nijland, R. Fluorescent reporters for markerless genomic integration in Staphylococcus aureus. Sci. Rep. 7, 43889 (2017).","journal-title":"Sci. Rep."},{"key":"2124_CR70","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.plasmid.2008.10.001","volume":"61","author":"RM Corrigan","year":"2009","unstructured":"Corrigan, R. M. & Foster, T. J. An improved tetracycline-inducible expression vector for Staphylococcus aureus. Plasmid 61, 126\u2013129 (2009).","journal-title":"Plasmid"},{"key":"2124_CR71","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676\u2013682 (2012).","journal-title":"Nat. Methods"},{"key":"2124_CR72","doi-asserted-by":"crossref","DOI":"10.1128\/mbio.02251-22","volume":"13","author":"O Rutschmann","year":"2022","unstructured":"Rutschmann, O., Toniolo, C. & McKinney, J. D. Preexisting heterogeneity of inducible nitric oxide synthase expression drives differential growth of Mycobacterium tuberculosis in macrophages. mBio 13, e0225122 (2022).","journal-title":"mBio"},{"key":"2124_CR73","first-page":"7.23.1","volume":"111","author":"DB Kuhns","year":"2015","unstructured":"Kuhns, D. B., Priel, D. A. L., Chu, J. & Zarember, K. A. Isolation and functional analysis of human neutrophils. Curr. Protoc. Immunol. 111, 7.23.1\u20137.23.16 (2015).","journal-title":"Curr. Protoc. Immunol."},{"key":"2124_CR74","doi-asserted-by":"publisher","DOI":"10.3791\/54368","author":"R Nistala","year":"2016","unstructured":"Nistala, R., Meuth, A., Smith, C. & Annayya, A. Reliable and high efficiency extraction of kidney immune cells. J. Vis. Exp. https:\/\/doi.org\/10.3791\/54368 (2016).","journal-title":"J. Vis. Exp."},{"key":"2124_CR75","doi-asserted-by":"crossref","first-page":"8173","DOI":"10.1073\/pnas.1509743112","volume":"112","author":"MA Lobritz","year":"2015","unstructured":"Lobritz, M. A. et al. Antibiotic efficacy is linked to bacterial cellular respiration. Proc. Natl Acad. Sci. USA 112, 8173\u20138180 (2015).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2124_CR76","doi-asserted-by":"crossref","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","volume":"51","author":"S Kim","year":"2023","unstructured":"Kim, S. et al. PubChem 2023 update. Nucleic Acids Res. 51, D1373\u2013D1380 (2023).","journal-title":"Nucleic Acids Res."},{"key":"2124_CR77","doi-asserted-by":"crossref","first-page":"D246","DOI":"10.1093\/nar\/gkx1158","volume":"46","author":"I Papatheodorou","year":"2018","unstructured":"Papatheodorou, I. et al. Expression Atlas: gene and protein expression across multiple studies and organisms. Nucleic Acids Res. 46, D246\u2013D251 (2018).","journal-title":"Nucleic Acids Res."},{"key":"2124_CR78","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","volume":"51","author":"D Szklarczyk","year":"2023","unstructured":"Szklarczyk, D. et al. The STRING database in 2023: protein\u2013protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51, D638\u2013D646 (2023).","journal-title":"Nucleic Acids Res."}],"container-title":["Nature Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02124-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02124-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02124-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T22:23:11Z","timestamp":1761949391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02124-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,10]]},"references-count":78,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["2124"],"URL":"https:\/\/doi.org\/10.1038\/s41564-025-02124-2","relation":{},"ISSN":["2058-5276"],"issn-type":[{"value":"2058-5276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,10]]},"assertion":[{"value":"18 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}