Waldor, Matthew KGrad, Yonatan HRubin, Daniel Hidemitsu Fujii2023-06-0220232023-04-112023-05Rubin, Daniel Hidemitsu Fujii. 2023. Mechanisms and acquisition of antibiotic resistance in N. gonorrhoeae. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.30316093https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37375474Neisseria gonorrhoeae, the causative agent of the human disease gonorrhea, has a substantial global burden of disease, causing more than 100 million cases a year. Throughout the antibiotic era, gonorrheal antibiotic resistance has emerged to every first-line agent used for treatment. One such agent is the antibiotic ciprofloxacin, which targets the DNA gyrase of gonorrhea. Here, we describe how metabolic variation in N. gonorrhoeae, as mediated by a single variant in a carbonic anhydrase, can drive fitness changes in the context of ciprofloxacin resistance-conferring mutations in DNA gyrase. Metabolic diversity may therefore be one driver of differential acquisition of resistance determinants. We further show that a new diagnostic that identifies such mutations in DNA gyrase may lead to diagnostic escape and cross-resistance to novel antibiotics targeting N. gonorrhoeae. In summary, the pathogenic environment, antibiotic treatment, and diagnostics – both old and new – shape the genomic landscape of N. gonorrhoeae.application/pdfenMicrobiologyThesis or Dissertation2023-06-020000-0002-6753-4213