RT Journal Article SR Electronic T1 Increased antibiotic susceptibility in Neisseria gonorrhoeae through adaptation to the cervical environment JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.07.896696 DO 10.1101/2020.01.07.896696 A1 Kevin C Ma A1 Tatum D Mortimer A1 Allison L Hicks A1 Nicole E Wheeler A1 Leonor Sánchez-Busó A1 Daniel Golparian A1 George Taiaroa A1 Daniel HF Rubin A1 Yi Wang A1 Deborah A Williamson A1 Magnus Unemo A1 Simon R Harris A1 Yonatan H Grad YR 2020 UL http://biorxiv.org/content/early/2020/01/08/2020.01.07.896696.abstract AB 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 on the largest collection of N. gonorrhoeae isolates to date (n=4882) 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 isolates relative to urethral isolates (odds ratio (OR) = 3.74, 95% CI [1.98-6.70]). In support of a model in which pump expression incurs a fitness cost in this niche, cervical isolates were also enriched relative to urethral isolates in LOF mutations in the mtrCDE activator mtrA (OR = 8.60, 95% CI [4.96-14.57]) and in farA, a subunit of the FarAB efflux pump (OR = 6.25, 95% CI [3.90-9.83]). In total, approximately 1 in 3 cervical isolates (36.4%) contained a LOF mutation in either the efflux pump components mtrC or farA or the activator mtrA. Our findings extend beyond N. gonorrhoeae to other Neisseria: mtrC LOF mutations are rare (<1%) in the primarily nasopharyngeal-colonizing N. meningitidis in a collection of 14,798 genomes but enriched in a heterosexual urethritis-associated lineage (8.6%, p = 9.90×10-5), indicating that efflux pump downregulation contributes broadly to the adaptation of pathogenic Neisseria to the female urogenital tract. 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.