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Gonorrhea is the second most commonly reported sexually transmitted infection in the United States, and rates have been rapidly climbing over the last decade. While antibiotic resistance is a major concern, as Neisseria gonorrhoeae has developed resistance to every antibiotic we’ve used to treat it, we also see reversions to susceptibility, and some isolates have minimum inhibitory concentrations (MICs) lower than what we would predict given the resistance alleles they encode. Here we performed a genome wide association study using genomic data and MICs from 4,852 N. gonorrhoeae clinical isolates to identify loci contributing to antibiotic susceptibility.

In our GWAS, we identified known resistance determinants such as mutations in 23S rRNA for azithromycin, mosaic penA for ceftriaxone, and mutations in gyrA for ciprofloxacin. However, we also found a 2bp deletion that causes a frameshift in mtrC that was associated with susceptibility to all three antibiotics. mtrC encodes a component of the Mtr efflux pump; overexpression of this pump is known to be associated with antibiotic resistance and has been shown to be have a fitness benefit in the mouse model of gonorrhea. However, the 2bp emerged many times throughout the phylogeny and was present in approximately 1 out of every 25 isolates in our dataset, suggesting that this mutation must be selected for in some environments.

We know that N. gonorrhoeae can infect multiple sites, including the cervix, urethra, rectum, and pharynx. Using the available patient metadata associated with our isolates, we looked for associations between the presence of the mtrC loss of function mutations and sexual behavior or site of infection. We found that mtrC loss of function was overrepresented in isolates from heterosexual patients and isolates from the cervix. We also found that loss of function mutations in the activator mtrA and in a component from another proton dependent efflux pump, farA, were also overrepresented in cervical isolates. We hypothesize that environmental conditions in the cervix (e.g. low oxygen, low pH) lead to a fitness cost for expression of these pumps.

This project is now published in Nature Communications!