{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T10:01:03Z","timestamp":1777802463276,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009108","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000}}],"reference-count":99,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UKRI-InnovateUK","award":["132854"],"award-info":[{"award-number":["132854"]}]},{"name":"UKRI-InnovateUK","award":["132854"],"award-info":[{"award-number":["132854"]}]},{"name":"UKRI-InnovateUK","award":["132854"],"award-info":[{"award-number":["132854"]}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/M027333\/1"],"award-info":[{"award-number":["EP\/M027333\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/M027333\/1"],"award-info":[{"award-number":["EP\/M027333\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/M027333\/1"],"award-info":[{"award-number":["EP\/M027333\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Republic of Turkey Ministry of National Education and Ministry of Agriculture and Forestry"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p><jats:italic>Staphylococcus aureus<\/jats:italic>is a serious human and animal pathogen threat exhibiting extraordinary capacity for acquiring new antibiotic resistance traits in the pathogen population worldwide.<\/jats:p><jats:p>The development of fast, affordable and effective diagnostic solutions capable of discriminating between antibiotic-resistant and susceptible<jats:italic>S<\/jats:italic>.<jats:italic>aureus<\/jats:italic>strains would be of huge benefit for effective disease detection and treatment. Here we develop a diagnostics solution that uses Matrix-Assisted Laser Desorption\/Ionisation\u2013Time of Flight Mass Spectrometry (MALDI-TOF) and machine learning, to identify signature profiles of antibiotic resistance to either multidrug or benzylpenicillin in<jats:italic>S<\/jats:italic>.<jats:italic>aureus<\/jats:italic>isolates. Using ten different supervised learning techniques, we have analysed a set of 82<jats:italic>S<\/jats:italic>.<jats:italic>aureus<\/jats:italic>isolates collected from 67 cows diagnosed with bovine mastitis across 24 farms. For the multidrug phenotyping analysis, LDA, linear SVM, RBF SVM, logistic regression, na\u00efve Bayes, MLP neural network and QDA had Cohen\u2019s kappa values over 85.00%. For the benzylpenicillin phenotyping analysis, RBF SVM, MLP neural network, na\u00efve Bayes, logistic regression, linear SVM, QDA, LDA, and random forests had Cohen\u2019s kappa values over 85.00%. For the benzylpenicillin the diagnostic systems achieved up to (mean result \u00b1 standard deviation over 30 runs on the test set): accuracy = 97.54% \u00b1 1.91%, sensitivity = 99.93% \u00b1 0.25%, specificity = 95.04% \u00b1 3.83%, and Cohen\u2019s kappa = 95.04% \u00b1 3.83%. Moreover, the diagnostic platform complemented by a protein-protein network and 3D structural protein information framework allowed the identification of five molecular determinants underlying the susceptible and resistant profiles. Four proteins were able to classify multidrug-resistant and susceptible strains with 96.81% \u00b1 0.43% accuracy. Five proteins, including the previous four, were able to classify benzylpenicillin resistant and susceptible strains with 97.54% \u00b1 1.91% accuracy. Our approach may open up new avenues for the development of a fast, affordable and effective day-to-day diagnostic solution, which would offer new opportunities for targeting resistant bacteria.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009108","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T17:40:33Z","timestamp":1623433233000},"page":"e1009108","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Mass spectrometry and machine learning for the accurate diagnosis of benzylpenicillin and multidrug resistance of Staphylococcus aureus in bovine mastitis"],"prefix":"10.1371","volume":"17","author":[{"given":"Necati","family":"Esener","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1396-9438","authenticated-orcid":true,"given":"Alexandre","family":"Maciel-Guerra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6037-0618","authenticated-orcid":true,"given":"Katharina","family":"Giebel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8152-0398","authenticated-orcid":true,"given":"Daniel","family":"Lea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6408-6443","authenticated-orcid":true,"given":"Martin J.","family":"Green","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Bradley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7733-906X","authenticated-orcid":true,"given":"Tania","family":"Dottorini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"issue":"9","key":"pcbi.1009108.ref001","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/s41559-018-0617-0","article-title":"Gene exchange drives the ecological success of a multi-host bacterial pathogen","volume":"2","author":"EJ Richardson","year":"2018","journal-title":"Nature Ecology & Evolution"},{"issue":"10","key":"pcbi.1009108.ref002","doi-asserted-by":"crossref","first-page":"9493","DOI":"10.3168\/jds.2018-14824","article-title":"Pathogen-specific production losses in bovine mastitis","volume":"101","author":"AM Heikkil\u00e4","year":"2018","journal-title":"Journal of dairy science"},{"issue":"3","key":"pcbi.1009108.ref003","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.vetimm.2011.08.022","article-title":"Host-response patterns of intramammary infections in dairy cows","volume":"144","author":"YH Schukken","year":"2011","journal-title":"Veterinary Immunology and Immunopathology"},{"issue":"2","key":"pcbi.1009108.ref004","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1099\/00222615-40-2-79","article-title":"Virulence factors involved in the pathogenesis of bovine intramammary infections due to Staphylococcus aureus","volume":"40","author":"L Sutra","year":"1994","journal-title":"Journal of Medical Microbiology"},{"key":"pcbi.1009108.ref005","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/tbed.12698","article-title":"Knowledge gaps and research priorities in Staphylococcus aureus mastitis control","volume":"65","author":"P Rainard","year":"2018","journal-title":"Transboundary and emerging diseases"},{"issue":"6","key":"pcbi.1009108.ref006","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.3168\/jds.S0022-0302(00)74988-5","article-title":"Antimicrobial susceptibility of Staphylococcus aureus isolated from bovine mastitis in Argentina","volume":"83","author":"E Gentilini","year":"2000","journal-title":"Journal of dairy science"},{"issue":"24","key":"pcbi.1009108.ref007","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1136\/vr.104986","article-title":"A survey of dairy cow farmers in the United Kingdom: knowledge, attitudes and practices surrounding antimicrobial use and resistance","volume":"183","author":"LE Higham","year":"2018","journal-title":"Veterinary Record."},{"issue":"3","key":"pcbi.1009108.ref008","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1089\/mdr.1998.4.247","article-title":"Development of Penicillin Resistance among Staphylococcus aureus Isolated from Bovine Mastitis in Denmark and Other Countries","volume":"4","author":"FM Aarestrup","year":"1998","journal-title":"Microbial Drug Resistance"},{"issue":"4","key":"pcbi.1009108.ref009","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1128\/CMR.10.4.781","article-title":"Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications","volume":"10","author":"HF Chambers","year":"1997","journal-title":"Clinical microbiology reviews"},{"issue":"1","key":"pcbi.1009108.ref010","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3184\/003685002783238870","article-title":"Methicillin resistance in Staphylococcus aureus: mechanisms and modulation","volume":"85","author":"PD Stapleton","year":"2002","journal-title":"Science progress"},{"issue":"1","key":"pcbi.1009108.ref011","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.tim.2013.11.003","article-title":"The emergence of mecC methicillin-resistant Staphylococcus aureus","volume":"22","author":"GK Paterson","year":"2014","journal-title":"Trends in microbiology"},{"issue":"8","key":"pcbi.1009108.ref012","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/S1473-3099(11)70126-8","article-title":"Meticillin-resistant Staphylococcus aureus with a novel mecA homologue in human and bovine populations in the UK and Denmark: a descriptive study","volume":"11","author":"L Garc\u00eda-\u00c1lvarez","year":"2011","journal-title":"The Lancet Infectious Diseases"},{"key":"pcbi.1009108.ref013","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0924-8579(00)00299-5","article-title":"Antibiotic resistance in staphylococci","volume":"16","author":"DM Livermore","year":"2000","journal-title":"International journal of antimicrobial agents"},{"issue":"8","key":"pcbi.1009108.ref014","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1111\/j.1469-0691.2012.03846.x","article-title":"Livestock-associated Staphylococcus aureus","volume":"18","author":"AC Fluit","year":"2012","journal-title":"Clinical Microbiology and Infection"},{"key":"pcbi.1009108.ref015","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.3389\/fmicb.2019.02136","article-title":"Livestock-associated methicillin-resistant Staphylococcus aureus from animals and animal products in the UK","volume":"10","author":"MF Anjum","year":"2019","journal-title":"Frontiers in microbiology"},{"issue":"2","key":"pcbi.1009108.ref016","doi-asserted-by":"crossref","first-page":"e1004564","DOI":"10.1371\/journal.ppat.1004564","article-title":"Livestock-associated Staphylococcus aureus: the United States experience","volume":"11","author":"TC Smith","year":"2015","journal-title":"PLoS Pathog"},{"issue":"50","key":"pcbi.1009108.ref017","doi-asserted-by":"crossref","first-page":"20337","DOI":"10.2807\/ese.17.50.20337-en","article-title":"First detection of livestock-associated meticillin-resistant Staphylococcus aureus CC398 in bulk tank milk in the United Kingdom, January to July 2012","volume":"17","author":"GK Paterson","year":"2012","journal-title":"Eurosurveillance"},{"issue":"4","key":"pcbi.1009108.ref018","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00356-13","article-title":"Livestock origin for a human pandemic clone of community-associated methicillin-resistant Staphylococcus aureus","volume":"4","author":"LE Spoor","year":"2013","journal-title":"MBio"},{"issue":"4","key":"pcbi.1009108.ref019","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1089\/mdr.1996.2.435","article-title":"Tracking the evolutionary origin of the methicillin resistance gene: cloning and sequencing of a homologue of mecA from a methicillin susceptible strain of Staphylococcus sciuri","volume":"2","author":"S Wu","year":"1996","journal-title":"Microbial drug resistance"},{"issue":"8","key":"pcbi.1009108.ref020","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1128\/AAC.00187-11","article-title":"Detection of staphylococcal cassette chromosome mec type XI carrying highly divergent mecA, mecI, mecR1, blaZ, and ccr genes in human clinical isolates of clonal complex 130 methicillin-resistant Staphylococcus aureus","volume":"55","author":"AC Shore","year":"2011","journal-title":"Antimicrobial agents and chemotherapy"},{"key":"pcbi.1009108.ref021","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.vetmic.2015.10.027","article-title":"MRSA colonization and infection among persons with occupational livestock exposure in Europe: prevalence, preventive options and evidence","volume":"200","author":"T Goerge","year":"2017","journal-title":"Veterinary microbiology"},{"key":"pcbi.1009108.ref022","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1146\/annurev-biochem-060614-034516","article-title":"Mechanisms of Methicillin Resistance in Staphylococcus aureus","volume":"84","author":"SJ Peacock","year":"2015","journal-title":"Annu Rev Biochem"},{"issue":"12","key":"pcbi.1009108.ref023","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.1016\/S2095-3119(16)61368-0","article-title":"Genetic characterization of antimicrobial resistance in Staphylococcus aureus isolated from bovine mastitis cases in Northwest China","volume":"15","author":"Y Feng","year":"2016","journal-title":"Journal of integrative agriculture"},{"issue":"1","key":"pcbi.1009108.ref024","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12917-020-2235-8","article-title":"Burden and antimicrobial resistance of S. aureus in dairy farms in Mekelle, Northern Ethiopia","volume":"16","author":"AA Kalayu","year":"2020","journal-title":"BMC Veterinary Research"},{"key":"pcbi.1009108.ref025","volume-title":"UK veterinary antibiotic resistance and sales surveillance report","author":"VM Directorate","year":"2018"},{"issue":"5","key":"pcbi.1009108.ref026","doi-asserted-by":"crossref","first-page":"565","DOI":"10.2217\/fmb.09.30","article-title":"Genetics of antimicrobial resistance in Staphylococcus aureus","volume":"4","author":"SO Jensen","year":"2009","journal-title":"Future Microbiol"},{"key":"pcbi.1009108.ref027","author":"A Pantosti","year":"2007","journal-title":"Mechanisms of antibiotic resistance in Staphylococcus aureus"},{"issue":"3","key":"pcbi.1009108.ref028","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1093\/femsre\/fux007","article-title":"Antibiotic resistance in Staphylococcus aureus. Current status and future prospects","volume":"41","author":"TJ Foster","year":"2017","journal-title":"FEMS Microbiology Reviews"},{"issue":"26","key":"pcbi.1009108.ref029","doi-asserted-by":"crossref","first-page":"9786","DOI":"10.1073\/pnas.0402521101","article-title":"Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance","volume":"101","author":"MT Holden","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pcbi.1009108.ref030","first-page":"49","article-title":"Current and Emerging Methods of Antibiotic Susceptibility Testing","volume":"9","author":"ZA Khan","year":"2019","journal-title":"Diagnostics (Basel, Switzerland)"},{"issue":"1","key":"pcbi.1009108.ref031","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1128\/CMR.00058-12","article-title":"Matrix-assisted laser desorption ionization\u2013time of flight (MALDI-TOF) mass spectrometry for detection of antibiotic resistance mechanisms: from research to routine diagnosis","volume":"26","author":"J Hrab\u00e1k","year":"2013","journal-title":"Clinical Microbiology Reviews"},{"key":"pcbi.1009108.ref032","first-page":"1","article-title":"Rapid detection of antibiotic resistance in positive blood cultures by MALDI-TOF MS and an automated and optimized MBT-ASTRA protocol for Escherichia coli and Klebsiella pneumoniae","volume":"2019","author":"C Axelsson","journal-title":"Infectious Diseases"},{"key":"pcbi.1009108.ref033","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.clinms.2019.06.002","article-title":"MALDI-TOF bacterial subtyping to detect antibiotic resistance","volume":"14","author":"M Cordovana","year":"2019","journal-title":"Clinical Mass Spectrometry"},{"issue":"1","key":"pcbi.1009108.ref034","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/s41598-018-37503-9","article-title":"Combining MALDI-TOF and genomics in the study of methicillin resistant and multidrug resistant Staphylococcus pseudintermedius in New Zealand","volume":"9","author":"S Nisa","year":"2019","journal-title":"Scientific Reports"},{"key":"pcbi.1009108.ref035","article-title":"Machine learning for microbial identification and antimicrobial susceptibility testing on MALDI-TOF mass spectra: a systematic review","author":"CV Weis","year":"2020","journal-title":"Clinical Microbiology and Infection"},{"issue":"3","key":"pcbi.1009108.ref036","doi-asserted-by":"crossref","first-page":"163","DOI":"10.4265\/bio.22.163","article-title":"Rapid Discrimination between Methicillin-Sensitive and Methicillin-Resistant Staphylococcus aureus Using MALDI-TOF Mass Spectrometry","volume":"22","author":"K Sogawa","year":"2017","journal-title":"Biocontrol Science"},{"issue":"4","key":"pcbi.1009108.ref037","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1128\/JCM.02428-15","article-title":"Rapid detection of vancomycin-intermediate Staphylococcus aureus by matrix-assisted laser desorption ionization\u2013time of flight mass spectrometry","volume":"54","author":"CA Mather","year":"2016","journal-title":"Journal of clinical microbiology"},{"key":"pcbi.1009108.ref038","author":"J Bai","year":"2017","journal-title":"Classification of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus Aureus Using an Improved Genetic Algorithm for Feature Selection Based on Mass Spectra2017"},{"issue":"6","key":"pcbi.1009108.ref039","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0218951","article-title":"MALDI-TOF mass spectrometry on intact bacteria combined with a refined analysis framework allows accurate classification of MSSA and MRSA","volume":"14","author":"W Tang","year":"2019","journal-title":"PloS one"},{"key":"pcbi.1009108.ref040","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.3389\/fmicb.2018.02393","article-title":"Rapid Detection of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Based on Matrix-Assisted Laser Desorption Ionization Time-of-Flight: Using a Machine Learning Approach and Unbiased Validation","volume":"9","author":"H-Y Wang","year":"2018","journal-title":"Frontiers in Microbiology"},{"issue":"3","key":"pcbi.1009108.ref041","doi-asserted-by":"crossref","first-page":"e0194212","DOI":"10.1371\/journal.pone.0194212","article-title":"Rapid and easy detection of low-level resistance to vancomycin in methicillin-resistant Staphylococcus aureus by matrix-assisted laser desorption ionization time-of-flight mass spectrometry","volume":"13","author":"K Asakura","year":"2018","journal-title":"PloS one"},{"key":"pcbi.1009108.ref042","article-title":"Machine Learning in Mass Spectrometry: A MALDI-TOF MS Approach to Phenotypic Antibacterial Screening","author":"LN van Oosten","year":"2020","journal-title":"Journal of Medicinal Chemistry"},{"issue":"1","key":"pcbi.1009108.ref043","first-page":"559","article-title":"Imbalanced-learn: A python toolbox to tackle the curse of imbalanced datasets in machine learning","volume":"18","author":"G Lema\u00eetre","year":"2017","journal-title":"The Journal of Machine Learning Research"},{"issue":"6","key":"pcbi.1009108.ref044","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1128\/JCM.00518-13","article-title":"Analysis of the matrix-assisted laser desorption ionization-time of flight mass spectrum of Staphylococcus aureus identifies mutations that allow differentiation of the main clonal lineages","volume":"51","author":"M Josten","year":"2013","journal-title":"J Clin Microbiol"},{"issue":"1","key":"pcbi.1009108.ref045","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ijmm.2010.06.002","article-title":"MALDI-TOF MS fingerprinting allows for discrimination of major methicillin-resistant Staphylococcus aureus lineages","volume":"301","author":"M Wolters","year":"2011","journal-title":"International Journal of Medical Microbiology"},{"issue":"15","key":"pcbi.1009108.ref046","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1002\/elps.201100480","article-title":"Characterization of S taphylococcus aureus strains isolated from I talian dairy products by MALDI-TOF mass fingerprinting","volume":"33","author":"K B\u00f6hme","year":"2012","journal-title":"Electrophoresis"},{"issue":"2","key":"pcbi.1009108.ref047","doi-asserted-by":"crossref","first-page":"161.e1","DOI":"10.1016\/j.cmi.2015.10.009","article-title":"Automated categorization of methicillin-resistant Staphylococcus aureus clinical isolates into different clonal complexes by MALDI-TOF mass spectrometry","volume":"22","author":"M Camoez","year":"2016","journal-title":"Clinical Microbiology and Infection"},{"issue":"3","key":"pcbi.1009108.ref048","doi-asserted-by":"crossref","first-page":"e00135","DOI":"10.1128\/mSphere.00135-17","article-title":"Heparin Mimics Extracellular DNA in Binding to Cell Surface-Localized Proteins and Promoting Staphylococcus aureus Biofilm Formation","volume":"2","author":"S Mishra","year":"2017","journal-title":"mSphere"},{"issue":"3","key":"pcbi.1009108.ref049","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.celrep.2016.09.040","article-title":"Systematic Genetic Screens Reveal the Dynamic Global Functional Organization of the Bacterial Translation Machinery","volume":"17","author":"A Gagarinova","year":"2016","journal-title":"Cell Rep"},{"issue":"8","key":"pcbi.1009108.ref050","doi-asserted-by":"crossref","first-page":"e0182800","DOI":"10.1371\/journal.pone.0182800","article-title":"The nucleoid protein Dps binds genomic DNA of Escherichia coli in a non-random manner","volume":"12","author":"SS Antipov","year":"2017","journal-title":"PLoS One"},{"issue":"23","key":"pcbi.1009108.ref051","doi-asserted-by":"crossref","first-page":"6116","DOI":"10.1128\/JB.00783-10","article-title":"Evidence from artificial septal targeting and site-directed mutagenesis that residues in the extracytoplasmic beta domain of DivIB mediate its interaction with the divisomal transpeptidase PBP 2B","volume":"192","author":"SL Rowland","year":"2010","journal-title":"J Bacteriol"},{"issue":"1","key":"pcbi.1009108.ref052","doi-asserted-by":"crossref","first-page":"5555","DOI":"10.1038\/s41598-017-05621-5","article-title":"Evolution of the Pseudomonas aeruginosa mutational resistome in an international Cystic Fibrosis clone","volume":"7","author":"C Lopez-Causape","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"pcbi.1009108.ref053","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0022-2836(03)00725-3","article-title":"Evidence of a thermal unfolding dimeric intermediate for the Escherichia coli histone-like HU proteins: thermodynamics and structure","volume":"331","author":"J Ramstein","year":"2003","journal-title":"J Mol Biol"},{"key":"pcbi.1009108.ref054","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1186\/1471-2164-15-529","article-title":"Comparative genomics of methicillin-resistant Staphylococcus aureus ST239: distinct geographical variants in Beijing and Hong Kong","volume":"15","author":"Z Wang","year":"2014","journal-title":"BMC Genomics"},{"key":"pcbi.1009108.ref055","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1093\/gbe\/evr092","article-title":"The distribution of mobile genetic elements (MGEs) in MRSA CC398 is associated with both host and country","volume":"3","author":"AJ McCarthy","year":"2011","journal-title":"Genome Biol Evol"},{"key":"pcbi.1009108.ref056","doi-asserted-by":"crossref","first-page":"e20420","DOI":"10.7554\/eLife.20420","article-title":"Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment","volume":"6","author":"JE Gomez","year":"2017","journal-title":"eLife"},{"key":"pcbi.1009108.ref057","first-page":"103","article-title":"The intrinsic resistome of bacterial pathogens","volume":"4","author":"J Olivares Pacheco","year":"2013","journal-title":"Frontiers in Microbiology"},{"issue":"5","key":"pcbi.1009108.ref058","doi-asserted-by":"crossref","first-page":"e01593","DOI":"10.1128\/mBio.01593-17","article-title":"Selective Proteomic Analysis of Antibiotic-Tolerant Cellular Subpopulations in Pseudomonas aeruginosa Biofilms","volume":"8","author":"BM Babin","year":"2017","journal-title":"mBio"},{"key":"pcbi.1009108.ref059","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1186\/1471-2180-10-287","article-title":"Impact of the Staphylococcus epidermidis LytSR two-component regulatory system on murein hydrolase activity, pyruvate utilization and global transcriptional profile","volume":"10","author":"T Zhu","year":"2010","journal-title":"BMC microbiology"},{"issue":"4","key":"pcbi.1009108.ref060","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1128\/AAC.00906-09","article-title":"Antibiotic sensitivity profiles determined with an Escherichia coli gene knockout collection: generating an antibiotic bar code","volume":"54","author":"A Liu","year":"2010","journal-title":"Antimicrobial agents and chemotherapy"},{"issue":"15","key":"pcbi.1009108.ref061","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1128\/JB.00348-09","article-title":"The Staphylococcus aureus LytSR two-component regulatory system affects biofilm formation","volume":"191","author":"BK Sharma-Kuinkel","year":"2009","journal-title":"Journal of bacteriology"},{"key":"pcbi.1009108.ref062","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/1471-2164-10-291","article-title":"Comprehensive identification of essential Staphylococcus aureus genes using Transposon-Mediated Differential Hybridisation (TMDH)","volume":"10","author":"RR Chaudhuri","year":"2009","journal-title":"BMC Genomics"},{"issue":"13","key":"pcbi.1009108.ref063","doi-asserted-by":"crossref","first-page":"4056","DOI":"10.1128\/JB.00117-09","article-title":"Transcriptome and functional analysis of the eukaryotic-type serine\/threonine kinase PknB in Staphylococcus aureus","volume":"191","author":"S Donat","year":"2009","journal-title":"Journal of bacteriology"},{"issue":"12","key":"pcbi.1009108.ref064","doi-asserted-by":"crossref","first-page":"5843","DOI":"10.1128\/AAC.00425-13","article-title":"Comprehensive Identification of Mutations Responsible for Heterogeneous Vancomycin-Intermediate <span class = \"named-content genus-species\" id = \"named-content-1\">Staphylococcus aureus (hVISA)-to-VISA Conversion in Laboratory-Generated VISA Strains Derived from hVISA Clinical Strain Mu3","volume":"57","author":"M Matsuo","year":"2013","journal-title":"Antimicrobial Agents and Chemotherapy"},{"issue":"10","key":"pcbi.1009108.ref065","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/s41587-020-0644-7","article-title":"Detection of SARS-CoV-2 in nasal swabs using MALDI-MS","volume":"38","author":"FM Nachtigall","year":"2020","journal-title":"Nature biotechnology"},{"issue":"1","key":"pcbi.1009108.ref066","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1186\/1471-2105-9-443","article-title":"Peak intensity prediction in MALDI-TOF mass spectrometry: A machine learning study to support quantitative proteomics","volume":"9","author":"W Timm","year":"2008","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"pcbi.1009108.ref067","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1186\/s12859-015-0752-4","article-title":"Mass-Up: an all-in-one open software application for MALDI-TOF mass spectrometry knowledge discovery","volume":"16","author":"H L\u00f3pez-Fern\u00e1ndez","year":"2015","journal-title":"BMC Bioinformatics"},{"issue":"1","key":"pcbi.1009108.ref068","first-page":"1","article-title":"A simpler method of preprocessing MALDI-TOF MS data for differential biomarker analysis: stem cell and melanoma cancer studies","volume":"8","author":"DL Tong","year":"2011","journal-title":"Clinical proteomics"},{"issue":"11","key":"pcbi.1009108.ref069","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0224365","article-title":"Machine learning algorithm validation with a limited sample size","volume":"14","author":"A Vabalas","year":"2019","journal-title":"PloS one"},{"key":"pcbi.1009108.ref070","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.mimet.2014.02.015","article-title":"Insufficient discriminatory power of MALDI-TOF mass spectrometry for typing of Enterococcus faecium and Staphylococcus aureus isolates","volume":"100","author":"P Lasch","year":"2014","journal-title":"Journal of Microbiological Methods"},{"key":"pcbi.1009108.ref071","author":"JL Watts","year":"2008","journal-title":"Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals; approved standard\u2014third edition"},{"key":"pcbi.1009108.ref072","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/B978-0-08-092407-6.50007-9","volume-title":"Nitrogen Isotope Techniques","author":"RL Mulvaney","year":"1993"},{"key":"pcbi.1009108.ref073","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.prevetmed.2017.05.015","article-title":"Prediction of Streptococcus uberis clinical mastitis risk using Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) in dairy herds","volume":"144","author":"SC Archer","year":"2017","journal-title":"Preventive veterinary medicine"},{"key":"pcbi.1009108.ref074","volume-title":"ClinProTools 3.0: User Manual","author":"Bruker Daltonik GmbH","year":"2011"},{"key":"pcbi.1009108.ref075","article-title":"Data mining concepts and techniques third edition","author":"J Han","year":"2011","journal-title":"Morgan Kaufmann"},{"issue":"3","key":"pcbi.1009108.ref076","first-page":"25","article-title":"Machine learning","volume":"20","author":"C Cortes","year":"1995","journal-title":"Support vector networks."},{"key":"pcbi.1009108.ref077","volume-title":"Classification and regression trees","author":"L Breiman","year":"1984"},{"issue":"1","key":"pcbi.1009108.ref078","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"L Breiman","year":"2001","journal-title":"Machine learning"},{"issue":"2","key":"pcbi.1009108.ref079","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1162\/neco.1989.1.2.281","article-title":"Fast learning in networks of locally-tuned processing units","volume":"1","author":"J Moody","year":"1989","journal-title":"Neural computation"},{"issue":"3","key":"pcbi.1009108.ref080","doi-asserted-by":"crossref","first-page":"349","DOI":"10.4310\/SII.2009.v2.n3.a8","article-title":"Multi-class adaboost","volume":"2","author":"T Hastie","year":"2009","journal-title":"Statistics and its Interface"},{"issue":"2","key":"pcbi.1009108.ref081","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1111\/j.2517-6161.1958.tb00292.x","article-title":"The regression analysis of binary sequences","volume":"20","author":"DR Cox","year":"1958","journal-title":"Journal of the Royal Statistical Society: Series B (Methodological)."},{"key":"pcbi.1009108.ref082","volume-title":"Discriminant analysis and statistical pattern recognition","author":"G McLachlan","year":"2004"},{"issue":"Oct","key":"pcbi.1009108.ref083","first-page":"2825","article-title":"Scikit-learn: Machine learning in Python","volume":"12","author":"F Pedregosa","year":"2011","journal-title":"Journal of machine learning research"},{"issue":"Jul","key":"pcbi.1009108.ref084","first-page":"2079","article-title":"On over-fitting in model selection and subsequent selection bias in performance evaluation","volume":"11","author":"GC Cawley","year":"2010","journal-title":"Journal of Machine Learning Research"},{"issue":"1","key":"pcbi.1009108.ref085","first-page":"475","article-title":"Empirical evaluation of resampling procedures for optimising SVM hyperparameters","volume":"18","author":"J Wainer","year":"2017","journal-title":"The Journal of Machine Learning Research"},{"issue":"22","key":"pcbi.1009108.ref086","doi-asserted-by":"crossref","first-page":"6292","DOI":"10.1128\/JB.01188-12","article-title":"Genome Sequence of <span class = \"named-content genus-species\" id = \"named-content-1\">Staphylococcus aureus Newbould 305, a Strain Associated with Mild Bovine Mastitis","volume":"194","author":"D Bouchard","year":"2012","journal-title":"Journal of Bacteriology"},{"key":"pcbi.1009108.ref087","doi-asserted-by":"crossref","DOI":"10.1385\/1592598900","author":"JM Walker","year":"2005","journal-title":"The proteomics protocols handbook: Springer"},{"issue":"12","key":"pcbi.1009108.ref088","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1074\/mcp.M600225-MCP200","article-title":"The proteomics of N-terminal methionine cleavage","volume":"5","author":"F Frottin","year":"2006","journal-title":"Mol Cell Proteomics"},{"issue":"1","key":"pcbi.1009108.ref089","doi-asserted-by":"crossref","first-page":"17517","DOI":"10.1038\/s41598-018-35867-6","article-title":"Discrimination of contagious and environmental strains of Streptococcus uberis in dairy herds by means of mass spectrometry and machine-learning","volume":"8","author":"N Esener","year":"2018","journal-title":"Scientific Reports."},{"issue":"D1","key":"pcbi.1009108.ref090","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"D Szklarczyk","year":"2018","journal-title":"Nucleic acids research"},{"issue":"11","key":"pcbi.1009108.ref091","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"P Shannon","year":"2003","journal-title":"Genome research"},{"issue":"5586","key":"pcbi.1009108.ref092","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1126\/science.1073374","article-title":"Hierarchical organization of modularity in metabolic networks","volume":"297","author":"E Ravasz","year":"2002","journal-title":"Science"},{"issue":"1","key":"pcbi.1009108.ref093","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1752-0509-1-24","article-title":"Understanding network concepts in modules","volume":"1","author":"J Dong","year":"2007","journal-title":"BMC Systems Biology"},{"issue":"11","key":"pcbi.1009108.ref094","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1093\/jac\/dks261","article-title":"Identification of acquired antimicrobial resistance genes","volume":"67","author":"E Zankari","year":"2012","journal-title":"J Antimicrob Chemother"},{"issue":"W1","key":"pcbi.1009108.ref095","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: homology modelling of protein structures and complexes","volume":"46","author":"A Waterhouse","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"S1","key":"pcbi.1009108.ref096","doi-asserted-by":"crossref","first-page":"S162","DOI":"10.1002\/elps.200900140","article-title":"Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: A historical perspective","volume":"30","author":"N Guex","year":"2009","journal-title":"ELECTROPHORESIS"},{"issue":"W1","key":"pcbi.1009108.ref097","doi-asserted-by":"crossref","first-page":"W174","DOI":"10.1093\/nar\/gkv342","article-title":"I-TASSER server: new development for protein structure and function predictions","volume":"43","author":"J Yang","year":"2015","journal-title":"Nucleic acids research"},{"issue":"13","key":"pcbi.1009108.ref098","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"},{"issue":"13","key":"pcbi.1009108.ref099","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1093\/bioinformatics\/btq249","article-title":"PSORTb 3.0: improved protein subcellular localization prediction with refined localization subcategories and predictive capabilities for all prokaryotes","volume":"26","author":"NY Yu","year":"2010","journal-title":"Bioinformatics"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009108","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T17:42:24Z","timestamp":1725212544000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009108"}},"subtitle":[],"editor":[{"given":"Mark","family":"Holmes","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,11]]},"references-count":99,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009108","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1009108","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,11]]}}}