Compensatory mutants in antibiotic-resistant strains of Neisseria gonorrhoeae that restore fitness

The emergence of ceftriaxone-resistant (CroR) Neisseria gonorrhoeae has led to the looming threat of untreatable gonorrhea. Whether Cro resistance is likely to spread can be predicted from studies that compare the relative fitness of susceptible and resistant strains that differ only in the penA gene that confers CroR. We showed that mosaic penA alleles found in CroR clinical isolates are outcompeted by the CroS parent strain in vitro and in vivo, but that compensatory mutations are selected during mouse infection that allow ceftriaxone resistance to be maintained by increasing bacterial fitness. One compensatory mutant that was studied in more detail had a mutation in acnB, which encodes the aconitase that functions in the TCA cycle. This study illustrates that compensatory mutations can be selected during infection, which we hypothesize may allow the spread of Cro resistance in nature. This study also provides novel insights into gonococcal metabolism and physiology.