Adaptation to the cervical environment is associated with increased antibiotic susceptibility in Neisseria gonorrhoeae

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.

Emergence and evolution of antimicrobial resistance genes and mutations in Neisseria gonorrhoeae

“…These newly sequenced genomes were combined with those of 1066 publicly available genomes from 14 studies spanning 35 countries: USA, Japan, Canada, UK, Spain, Brazil, Portugal, New Zealand, Hungary, Norway, Ireland, Greece, Sweden, Slovenia, Germany, Poland, Belarus, Denmark, Slovakia, Belgium, Australia, Austria, Italy, Netherlands, France, Cyprus, Latvia, Malta, Russia, Philippines, Bulgaria, Chile, India, Finland, and Estonia (ordered by frequency) [ 9 , 11 , 13 – 23 ] (see Additional file 2 : Table S1 for details). The publicly available genomes were selected based on a tree constructed in our previous study [ 24 ] such that they formed a group at the core-genome level.…”

Associations between antimicrobial susceptibility/resistance of Neisseria gonorrhoeae isolates in European Union/European Economic Area and patients’ gender, sexual orientation and anatomical site of infection, 2009–2016

“…In Australia, significant differences in levels of resistance and decreased susceptibility were identified from gonococcal isolates derived from males versus females for all antimicrobials assessed [ 36 ]. Furthermore, it was recently suggested that genomic adaptation of gonococcal strains to the cervical environment is associated with increased antimicrobial susceptibility [ 37 ]. Regarding anatomical site of infection, pharyngeal gonorrhoea has been more common among MSM and gonococcal resistance to β-lactam antimicrobials, including the ESCs, may emerge in the pharynx through the acquisition of genetic AMR determinants from non-gonococcal commensal Neisseria species.…”

Genomic analysis of the meningococcal ST-4821 complex–Western clade, potential sexual transmission and predicted antibiotic susceptibility and vaccine coverage

“…Interestingly, lineage 2c also included a rare isolate lacking an fhbp gene and therefore unable to express fHbp which has also previously been implicated in adaptation to the anogenital niche [ 18 ]. None of the anogenital isolates possessed LOF mutations in mtrC that have been associated with cervical infection in gonococci and urogenitally adapted meningococci from uretheritis outbreaks among heterosexual males [ 19 ]. One possible explanation for this is that cc4821 isolates were all isolated from MSM and the cervix may not have been encountered in recent ancestral isolates.…”

“…A recent study in gonococci found an association between loss of function (LOF) mutation in the efflux pump component, MtrC, and cervical infection. This extended to US_NmUC in which 8.7% of isolates possessed LOF mutations versus 0.62% in a large invasive disease collection [ 19 ].…”