Abstract
Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates. This enrichment holds true for LOF mutations in another efflux pump, farAB, and in urogenitally-adapted versus typical N. meningitidis, providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria. Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility.
Highlights
Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance
To directly test the hypothesis that the two base pair deletion contributed to increased susceptibility for the panel of antibiotics we examined, we complemented the mutation in a clinical isolate belonging to the multidrug-resistant lineage ST-190123 and observed significant increases in minimum inhibitory concentrations (MICs) for all three antibiotics, as predicted by the genome-wide association study (GWAS)
In an era in which widespread antimicrobial pressure has led to the emergence of extensively drug-resistant N. gonorrhoeae[46], isolates that appear to have reverted to susceptibility still arise[9,10], demonstrating that antibiotic and host environmental pressures interact to shape the evolution of N. gonorrhoeae
Summary
Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. We used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates This enrichment holds true for LOF mutations in another efflux pump, farAB, and in urogenitally-adapted versus typical N. meningitidis, providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria. Despite the deeply concerning increase in antibiotic resistance reported in gonococcal populations globally[8], some clinical isolates of N. gonorrhoeae have become more susceptible to antibiotics[9,10] This unexpected phenomenon prompts questions about which environmental pressures could be drivers of increased susceptibility and the mechanisms by which suppression or reversion of resistance may occur. Our findings demonstrate how shifts in environmental pressures experienced by pathogenic Neisseria can lead to loss of efflux pump function and suppression of antibiotic resistance
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