{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T19:13:00Z","timestamp":1783969980796,"version":"3.55.0"},"reference-count":70,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T00:00:00Z","timestamp":1668470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Staphylococcus aureus (S. aureus) is a frequent cause of eye infections with some isolates exhibiting increased antimicrobial resistance to commonly prescribed antibiotics. The increasing resistance of ocular S. aureus to ciprofloxacin is a serious concern as it is a commonly used as a first line antibiotic to treat S. aureus keratitis. This study aimed to analyse genetic mutations in the genomes of 25 S. aureus isolates from infections or non-infectious ocular conditions from the USA and Australia and their relationship to ciprofloxacin resistance. Overall, 14\/25 isolates were phenotypically resistant to ciprofloxacin. All isolates were analyzed for mutations in their quinolone resistance-determining regions (QRDRs) and efflux pump genes. Of the fourteen resistant isolates, 9\/14 had ciprofloxacin resistance mutations within their QRDRs, at codons 80 or 84 within the parC subunit and codon 84 within the gyrA subunit of DNA gyrase. The highest resistance (MIC = 2560 \u03bcg\/mL) was associated with two SNPs in both gyrA and parC. Other resistant isolates (3\/14) had mutations within norB. Mutations in genes of other efflux pumps and their regulator (norA, norC, mepA, mdeA, sepA, sdrM, mepR, arlR, and arlS) or the DNA mismatch repair (MMR) system (mutL and mutS) were not associated with increased resistance to ciprofloxacin. The functional mutations associated with ciprofloxacin resistance in QRDRs (gyrA and parC) and norB suggests that these are the most common reasons for ciprofloxacin resistance in ocular isolates. Novel SNPs of gyrA Glu-88-Leu, Asn-860-Thr and Thr-845-Ala and IIe-855-Met, identified in this study, need further gene knock out\/in studies to better understand their effect on ciprofloxacin resistance.<\/jats:p>","DOI":"10.3390\/pathogens11111354","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:24:53Z","timestamp":1668565493000},"page":"1354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Relationship between Ciprofloxacin Resistance and Genotypic Changes in S. aureus Ocular Isolates"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4178-0114","authenticated-orcid":false,"given":"Madeeha","family":"Afzal","sequence":"first","affiliation":[{"name":"School of Optometry and Vision Sciences, University of New South Wales, Sydney, NSW 2041, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8248-6379","authenticated-orcid":false,"given":"Ajay Kumar","family":"Vijay","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Sciences, University of New South Wales, Sydney, NSW 2041, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7203-5443","authenticated-orcid":false,"given":"Fiona","family":"Stapleton","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Sciences, University of New South Wales, Sydney, NSW 2041, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3842-7563","authenticated-orcid":false,"given":"Mark","family":"Willcox","sequence":"additional","affiliation":[{"name":"School of Optometry and Vision Sciences, University of New South Wales, Sydney, NSW 2041, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus infections","volume":"339","author":"Lowy","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S1473-3099(05)70295-4","article-title":"The role of nasal carriage in Staphylococcus aureus infections","volume":"5","author":"Wertheim","year":"2005","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1001\/jama.2013.280318","article-title":"Conjunctivitis: A systematic review of diagnosis and treatment","volume":"310","author":"Azari","year":"2013","journal-title":"JAMA"},{"key":"ref_4","first-page":"160","article-title":"Infiltrative keratitis with contact lens wear\u2014A review","volume":"66","author":"Snyder","year":"1995","journal-title":"J. Am. Optom. Assoc."},{"key":"ref_5","first-page":"41","article-title":"Peripheral corneal infiltrates associated with contact lens wear","volume":"22","author":"Suchecki","year":"1996","journal-title":"CLAO J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1097\/00003226-200307000-00009","article-title":"Clinical characterization of corneal infiltrative events observed with soft contact lens wear","volume":"22","author":"Sweeney","year":"2003","journal-title":"Cornea"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1172\/JCI18535","article-title":"Antimicrobial resistance: The example of Staphylococcus aureus","volume":"111","author":"Lowy","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"76","DOI":"10.4103\/jms.jms_25_17","article-title":"World health organization releases global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibioti","volume":"32","author":"Shrivastava","year":"2018","journal-title":"J. Med. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3389\/fcimb.2020.00107","article-title":"Prevalence and Therapies of Antibiotic-Resistance in Staphylococcus aureus","volume":"10","author":"Guo","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"747","DOI":"10.2165\/00003495-200161060-00004","article-title":"Fluoroquinolones: Place in ocular therapy","volume":"61","author":"Smith","year":"2001","journal-title":"Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"137","DOI":"10.18773\/austprescr.2015.049","article-title":"Therapeutic Guidelines: Antibiotics","volume":"38","author":"Alam","year":"2015","journal-title":"Aust. Prescr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1093\/clinids\/24.Supplement_1.S67","article-title":"Trends in bacterial resistance to fluoroquinolones","volume":"24","author":"Acar","year":"1997","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/jac\/26.suppl_F.165","article-title":"Emergent resistance to ciprofloxacin amongst Pseudomonas aeruginosa and Staphylococcus aureus: Clinical significance and therapeutic approaches","volume":"26","author":"Ball","year":"1990","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1128\/AAC.33.4.593","article-title":"Widespread quinolone resistance among methicillin-resistant Staphylococcus aureus isolates in a general hospital","volume":"33","author":"Shalit","year":"1989","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Werner, N.L., Hecker, M.T., Sethi, A.K., and Donskey, C.J. (2011). Unnecessary use of fluoroquinolone antibiotics in hospitalized patients. BMC Infect. Dis., 11.","DOI":"10.1186\/1471-2334-11-187"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1177\/112067210501500104","article-title":"Infectious keratitis in South Australia: Emerging resistance to cephazolin","volume":"15","author":"Leibovitch","year":"2005","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1442-9071.2006.01143.x","article-title":"Bacteria commonly isolated from keratitis specimens retain antibiotic susceptibility to fluoroquinolones and gentamicin plus cephalothin","volume":"34","author":"Ly","year":"2006","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1071\/HI15014","article-title":"Rising fluoroquinolone resistance rates in corneal isolates: Implications for the wider use of antibiotics within the community","volume":"20","author":"Samarawickrama","year":"2015","journal-title":"Healthc. Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/ceo.13364","article-title":"Keratitis antimicrobial resistance surveillance program, Sydney, Australia: 2016 Annual Report","volume":"47","author":"Watson","year":"2019","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2147\/OPTO.S189115","article-title":"Antibiotic resistance among ocular pathogens: Current trends from the ARMOR surveillance study (2009\u20132016)","volume":"11","author":"Thomas","year":"2019","journal-title":"Clin. Optom."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Afzal, M., Vijay, A.K., Stapleton, F., and Willcox, M.D.P. (2021). Susceptibility of Ocular Staphylococcus aureus to Antibiotics and Multipurpose Disinfecting Solutions. Antibiotics, 10.","DOI":"10.3390\/antibiotics10101203"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1128\/AAC.34.6.1271","article-title":"Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli","volume":"34","author":"Yoshida","year":"1990","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1128\/AAC.35.8.1647","article-title":"Quinolone resistance-determining region in the DNA gyrase gyrB gene of Escherichia coli","volume":"35","author":"Yoshida","year":"1991","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1128\/AAC.39.12.2650","article-title":"Inducible NorA-mediated multidrug resistance in Staphylococcus aureus","volume":"39","author":"Kaatz","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1128\/AAC.37.5.1086","article-title":"Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus","volume":"37","author":"Kaatz","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7123","DOI":"10.1128\/JB.00655-08","article-title":"NorB, an efflux pump in Staphylococcus aureus strain MW2, contributes to bacterial fitness in abscesses","volume":"190","author":"Ding","year":"2008","journal-title":"J. Bacteriol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1128\/JB.187.7.2395-2405.2005","article-title":"MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus","volume":"187","author":"Dunman","year":"2005","journal-title":"J. Bacteriol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1128\/AAC.50.3.1104-1107.2006","article-title":"NorC, a new efflux pump regulated by MgrA of Staphylococcus aureus","volume":"50","author":"Strahilevitz","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1128\/AAC.49.1.161-169.2005","article-title":"Effect of promoter region mutations and mgrA overexpression on transcription of norA, which encodes a Staphylococcus aureus multidrug efflux transporter","volume":"49","author":"Kaatz","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1128\/JB.185.10.3127-3138.2003","article-title":"Characterization of NorR protein, a multifunctional regulator of norA expression in Staphylococcus aureus","volume":"185","author":"Zhang","year":"2003","journal-title":"J. Bacteriol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1128\/AAC.49.5.1857-1864.2005","article-title":"Multidrug resistance in Staphylococcus aureus due to overexpression of a novel multidrug and toxin extrusion (MATE) transport protein","volume":"49","author":"Kaatz","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1128\/AAC.49.5.1865-1871.2005","article-title":"A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline","volume":"49","author":"McAleese","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1128\/AAC.48.3.909-917.2004","article-title":"Novel chromosomally encoded multidrug efflux transporter MdeA in Staphylococcus aureus","volume":"48","author":"Huang","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1248\/bpb.29.801","article-title":"Functional gene cloning and characterization of MdeA, a multidrug efflux pump from Staphylococcus aureus","volume":"29","author":"Yamada","year":"2006","journal-title":"Biol. Pharm. Bull."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.micpath.2017.08.026","article-title":"Frequency of efflux pump genes mediating ciprofloxacin and antiseptic resistance in methicillin-resistant Staphylococcus aureus isolates","volume":"111","author":"Hassanzadeh","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1248\/bpb.29.554","article-title":"Gene cloning and characterization of SdrM, a chromosomally-encoded multidrug efflux pump, from Staphylococcus aureus","volume":"29","author":"Yamada","year":"2006","journal-title":"Biol. Pharm. Bull."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/j.1751-7915.2008.00063.x","article-title":"Mechanism of action of and resistance to quinolones","volume":"2","author":"Madurga","year":"2009","journal-title":"Microb. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1128\/JB.182.3.664-671.2000","article-title":"Expression of the multidrug resistance transporter NorA from Staphylococcus aureus is modified by a two-component regulatory system","volume":"182","author":"Fournier","year":"2000","journal-title":"J. Bacteriol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/S1473-3099(02)00369-9","article-title":"Fluoroquinolone resistance among Gram-positive cocci","volume":"2","author":"Hooper","year":"2002","journal-title":"Lancet Infect. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1128\/AAC.40.8.1881","article-title":"Quinolone resistance mutations in topoisomerase IV: Relationship to the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase is the secondary target of fluoroquinolones in Staphylococcus aureus","volume":"40","author":"Ng","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1007\/s10096-002-0788-z","article-title":"Activity of quinolones against gram-positive cocci: Mechanisms of drug action and bacterial resistance","volume":"21","author":"Schmitz","year":"2002","journal-title":"Eur. J. Clin. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1128\/AAC.39.7.1414","article-title":"Incidence of various gyrA mutants in 451 Staphylococcus aureus strains isolated in Japan and their susceptibilities to 10 fluoroquinolones","volume":"39","author":"Takenouchi","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1128\/AAC.42.5.1249","article-title":"Characterization of grlA, grlB, gyrA, and gyrB mutations in 116 unrelated isolates of Staphylococcus aureus and effects of mutations on ciprofloxacin MIC","volume":"42","author":"Schmitz","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1128\/AAC.39.7.1554","article-title":"Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus","volume":"39","author":"Ferrero","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1086\/378810","article-title":"Hypermutation as a factor contributing to the acquisition of antimicrobial resistance","volume":"37","year":"2003","journal-title":"Clin. Infect. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1128\/AAC.46.3.863-865.2002","article-title":"Mutator bacteria as a risk factor in treatment of infectious diseases","volume":"46","author":"Giraud","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1146\/annurev.micro.50.1.625","article-title":"Spontaneous mutators in bacteria: Insights into pathways of mutagenesis and repair","volume":"50","author":"Miller","year":"1996","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1086\/374937","article-title":"High rate of macrolide resistance in Staphylococcus aureus strains from patients with cystic fibrosis reveals high proportions of hypermutable strains","volume":"187","author":"Prunier","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.ge.25.120191.001305","article-title":"Mechanisms and biological effects of mismatch repair","volume":"25","author":"Modrich","year":"1991","journal-title":"Annu. Rev. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S1368-7646(03)00041-4","article-title":"The role of mutators in the emergence of antibiotic-resistant bacteria","volume":"6","author":"Chopra","year":"2003","journal-title":"Drug Resist. Updates"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1093\/jac\/dkf118","article-title":"Insertional inactivation of mutS in Staphylococcus aureus reveals potential for elevated mutation frequencies, although the prevalence of mutators in clinical isolates is low","volume":"50","author":"Chopra","year":"2002","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1046\/j.1469-0691.2000.006006331.x","article-title":"In vitro activity of linezolid against staphylococci","volume":"6","author":"Cuny","year":"2000","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3229","DOI":"10.1128\/AAC.44.11.3229-3231.2000","article-title":"Development of resistance to ciprofloxacin, rifampin, and mupirocin in methicillin-susceptible and -resistant Staphylococcus aureus isolates","volume":"44","author":"Schmitz","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0921-8777(01)00088-X","article-title":"Molecular mechanisms of DNA mismatch repair","volume":"486","author":"Hsieh","year":"2001","journal-title":"Mutat. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/342396a0","article-title":"The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants","volume":"342","author":"Rayssiguier","year":"1989","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1167\/tvst.11.7.5","article-title":"Virulence Genes of Staphylococcus aureus Associated With Keratitis, Conjunctivitis, and Contact Lens-Associated Inflammation","volume":"11","author":"Afzal","year":"2022","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Afzal, M., Vijay, A.K., Stapleton, F., and Willcox, M.D.P. (2022). Genomics of Staphylococcus aureus Strains Isolated from Infectious and Non-Infectious Ocular Conditions. Antibiotics, 11.","DOI":"10.3390\/antibiotics11081011"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e01864-19","DOI":"10.1128\/JCM.01864-19","article-title":"The Clinical and Laboratory Standards Institute Subcommittee on Antimicrobial Susceptibility Testing: 30th ed CLSI supplement M100 Clinical and Labortary Stranadrads Institute","volume":"58","author":"Weinstein","year":"2020","journal-title":"J. Clin. Microbiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Nurk, S., Bankevich, A., Antipov, D., Gurevich, A., Korobeynikov, A., Lapidus, A., Prjibelsky, A., Pyshkin, A., Sirotkin, A., and Sirotkin, Y. (2013). Assembling Genomes and Mini-Metagenomes from Highly Chimeric Reads, Springer.","DOI":"10.1007\/978-3-642-37195-0_13"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1093\/bioinformatics\/btu153","article-title":"Prokka: Rapid prokaryotic genome annotation","volume":"30","author":"Seemann","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1101\/gr.176601","article-title":"Predicting deleterious amino acid substitutions","volume":"11","author":"Ng","year":"2001","journal-title":"Genome Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1159\/000330858","article-title":"Topoisomerase mutations that are associated with high-level resistance to earlier fluoroquinolones in Staphylococcus aureus have less effect on the antibacterial activity of besifloxacin","volume":"57","author":"Sanfilippo","year":"2011","journal-title":"Chemotherapy"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1128\/AAC.40.12.2714","article-title":"Differential behaviors of Staphylococcus aureus and Escherichia coli type II DNA topoisomerases","volume":"40","author":"Blanche","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jgar.2019.05.026","article-title":"Genetic mutations in the quinolone resistance-determining region are related to changes in the epidemiological profile of methicillin-resistant Staphylococcus aureus isolates","volume":"19","author":"Cavalcante","year":"2019","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/j.1365-2958.1994.tb00458.x","article-title":"Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: A primary target of fluoroquinolones","volume":"13","author":"Ferrero","year":"1994","journal-title":"Mol. Microbiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1128\/AAC.40.5.1157","article-title":"Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus","volume":"40","author":"Yamagishi","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3390\/antibiotics2010083","article-title":"Resistance to antimicrobials mediated by efflux pumps in Staphylococcus aureus","volume":"2","author":"Costa","year":"2013","journal-title":"Antibiotics"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e00894-18","DOI":"10.1128\/mBio.00894-18","article-title":"Increased Usage of Antiseptics Is Associated with Reduced Susceptibility in Clinical Isolates of Staphylococcus aureus","volume":"9","author":"Hardy","year":"2018","journal-title":"mBio"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Smits, T.H.M. (2019). The importance of genome sequence quality to microbial comparative genomics. BMC Genom., 20.","DOI":"10.1186\/s12864-019-6014-5"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/11\/1354\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:18:34Z","timestamp":1760145514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/11\/1354"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,15]]},"references-count":70,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["pathogens11111354"],"URL":"https:\/\/doi.org\/10.3390\/pathogens11111354","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,15]]}}}