{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:44:45Z","timestamp":1793277885600,"version":"4.5.0"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p><jats:italic>Salmonella enterica<\/jats:italic> is a common foodborne pathogen that causes intestinal illness varying from mild gastroenteritis to life-threatening systemic infections. The frequency of outbreaks due to multidrug-resistant <jats:italic>Salmonella<\/jats:italic> has been increased in the past few years with increasing numbers of annual deaths. Therefore, new strategies to control the spread of antimicrobial resistance are required. In this work, we found that N-acetyl cysteine (NAC) inhibits <jats:italic>S<\/jats:italic>. <jats:italic>enterica<\/jats:italic> at MIC of 3 mg ml<jats:sup>-1<\/jats:sup> and synergistically activates the bactericidal activities of common antibiotics from three-fold for ampicillin and apramycin up to1000-fold for gentamycin. In addition, NAC inhibits the expression of virulence genes at sub-inhibitory concentrations in a dose-dependent manner. The whole-genome sequencing revealed that continuous exposure of <jats:italic>S<\/jats:italic>. <jats:italic>enterica<\/jats:italic> to NAC leads to the development of resistance; these resistant strains are attenuated for virulence. These results suggest that NAC may be a promising adjuvant to antibiotics for treating <jats:italic>S<\/jats:italic>. <jats:italic>enterica<\/jats:italic> in combination with other antibiotics.<\/jats:p>","DOI":"10.1371\/journal.pone.0313508","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T18:25:51Z","timestamp":1736274351000},"page":"e0313508","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["N-Acetyl cysteine exhibits antimicrobial and anti-virulence activity against Salmonella 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Su","year":"2014","journal-title":"Artif Cells Nanomed Biotechnol"},{"issue":"2","key":"pone.0313508.ref035","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S1995-7645(14)60010-9","article-title":"Hepatic effect of NAC on sevear acute pancteatise of rats","volume":"7","author":"F Chen","year":"2014","journal-title":"Asian Pac J Trop Med"},{"issue":"12","key":"pone.0313508.ref036","first-page":"15","article-title":"N-acetyl cysteine substantially enhances the antimicrobial activity of zinc oxide nanoparticles against multidrug resistant pathogens","volume":"2","author":"ME Selwan Hamed","year":"2015","journal-title":"International Journal of Advanced Research in Biological Sciences"},{"issue":"3","key":"pone.0313508.ref037","doi-asserted-by":"crossref","DOI":"10.3390\/pathogens8030120","article-title":"N-acetyl Cysteine Coated Gallium Particles Demonstrate High Potency against Pseudomonas aeruginosa PAO1","volume":"8","author":"M Young","year":"2019","journal-title":"Pathogens"},{"issue":"2","key":"pone.0313508.ref038","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ijpharm.2017.03.079","article-title":"Clarithromycin and N-acetylcysteine co-spray-dried powders for pulmonary drug delivery: A focus on drug solubility","volume":"533","author":"MD Manniello","year":"2017","journal-title":"Int J Pharm"},{"issue":"1","key":"pone.0313508.ref039","doi-asserted-by":"crossref","first-page":"212","DOI":"10.21037\/jtd.2017.11.130","article-title":"In vitro effects of N-acetylcysteine alone and combined with tigecycline on planktonic cells and biofilms of Acinetobacter baumannii","volume":"10","author":"J Feng","year":"2018","journal-title":"J Thorac Dis"},{"issue":"10","key":"pone.0313508.ref040","doi-asserted-by":"crossref","first-page":"e0203941","DOI":"10.1371\/journal.pone.0203941","article-title":"In vitro activity of N-acetylcysteine against Stenotrophomonas maltophilia and Burkholderia cepacia 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and N-acetylcysteine to ameliorate ototoxicity in the rat cochlea","volume":"358","author":"F Garcia-Alcantara","year":"2018","journal-title":"Hear Res"},{"issue":"1","key":"pone.0313508.ref044","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1046\/j.1365-2958.1999.01461.x","article-title":"Inducible prophages contribute to Salmonella virulence in mice","volume":"33","author":"N Figueroa-Bossi","year":"1999","journal-title":"Mol Microbiol"},{"issue":"1","key":"pone.0313508.ref045","first-page":"1","article-title":"Bacteriophage-encoded type III effectors in Salmonella enterica subspecies 1 serovar Typhimurium","volume":"5","author":"K Ehrbar","year":"2005","journal-title":"Infect Genet Evol"},{"issue":"6","key":"pone.0313508.ref046","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3390\/cells13060514","article-title":"Diverse prophage elements of Salmonella enterica serovars show potential roles in bacterial pathogenicity","volume":"13","author":"K Andrews","year":"2024","journal-title":"Cells"},{"issue":"1","key":"pone.0313508.ref047","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s12866-019-1583-7","article-title":"Synergistic action of SPI-1 gene expression in Salmonella enterica serovar typhimurium through transcriptional crosstalk with the flagellar system","volume":"19","author":"S Hamed","year":"2019","journal-title":"BMC Microbiol"},{"key":"pone.0313508.ref048","unstructured":"CLSI. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility test for bacteria that grow aerobically. Wayne, Pennsylvania, USA: CLSI; 2015."},{"key":"pone.0313508.ref049","first-page":"330","volume-title":"Antibiotics in laboratory medicine","author":"GM Eliopoulos","year":"1996","edition":"4"},{"issue":"5","key":"pone.0313508.ref050","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"H Li","year":"2010","journal-title":"Bioinform"},{"issue":"21","key":"pone.0313508.ref051","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1093\/bioinformatics\/btr509","article-title":"A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data","volume":"27","author":"H. Li","year":"2011","journal-title":"Bioinform"},{"issue":"2","key":"pone.0313508.ref052","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"P Cingolani","year":"2012","journal-title":"Fly (Austin)"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0313508","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T18:26:20Z","timestamp":1736274380000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0313508"}},"subtitle":[],"editor":[{"given":"Anujith","family":"Kumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,7]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0313508","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,7]]}}}