Genome-wide association identifies antibiotic resistance and susceptibility mutations in Neisseria gonorrhoeae

Abstract

The emergence of resistance to multiple frontline antibiotics complicates treatment of Neisseria gonorrhoeae, the etiologic agent of gonorrhea. Characterizing the molecular mechanisms of resistance will inform the development of sequence-based diagnostics and improve our understanding of how gonococci respond to host and drug pressures. Here, we conduct several bacterial genome-wide association studies (GWASes) that incorporate pan-genomic diversity and stringent control for population structure on the largest assembled dataset to date of gonococcal genome sequences and antibiotic testing data. In Chapter 2, we describe how we identified a single mutation associated with increased susceptibility to multiple antibiotics using GWAS and then characterized the environments it arises in using host metadata. In Chapter 3, we use genomic epidemiology in combination with insights from structural biology to identify clinical isolates with rare mutations conferring increased antibiotic resistance. In Chapter 4, we demonstrate how extending standard GWAS models by adjusting for the effect of known resistance genes results in substantially decreased false positives and increased power to detect new resistance genes. The results of these studies will advance our understanding of the evolution of N. gonorrhoeae and provide new strategies for interrogating the genetic basis of antibiotic resistance and susceptibility broadly in microbial pathogens.