| Summary: | <i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a frequent cause of eye infections with some isolates exhibiting increased antimicrobial resistance to commonly prescribed antibiotics. The increasing resistance of ocular <i>S. aureus</i> to ciprofloxacin is a serious concern as it is a commonly used as a first line antibiotic to treat <i>S. aureus</i> keratitis. This study aimed to analyse genetic mutations in the genomes of 25 <i>S. aureus</i> 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 <i>parC</i> subunit and codon 84 within the <i>gyrA</i> subunit of DNA gyrase. The highest resistance (MIC = 2560 μg/mL) was associated with two SNPs in both <i>gyrA</i> and <i>parC</i>. Other resistant isolates (3/14) had mutations within <i>norB.</i> Mutations in genes of other efflux pumps and their regulator (<i>norA</i>, <i>norC</i>, <i>mepA</i>, <i>mdeA</i>, <i>sepA</i>, <i>sdrM</i>, <i>mepR</i>, <i>arlR</i>, and <i>arlS</i>) or the DNA mismatch repair (MMR) system (<i>mutL</i> and <i>mutS</i>) were not associated with increased resistance to ciprofloxacin. The functional mutations associated with ciprofloxacin resistance in QRDRs (<i>gyrA</i> and <i>parC</i>) and <i>norB</i> suggests that these are the most common reasons for ciprofloxacin resistance in ocular isolates. Novel SNPs of <i>gyrA</i> 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.
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