Mosaic Drug Efflux Gene Sequences from Commensal Neisseria Can Lead to Low-Level Azithromycin Resistance Expressed by Neisseria gonorrhoeae Clinical Isolates

Abstract

In a previous mBio article, Wadsworth and colleagues (mBio 9:e01419-18, 2018, https://doi.org/10.1128/mBio.01419-18) described Neisseria gonorrhoeae isolates that express low levels of azithromycin (Azi) resistance. Whole-genome sequencing and bioinformatic analysis suggested that the isolates had acquired DNA from commensal Neisseria spp. that caused numerous nucleotide changes in the mtr locus, which contains genes for a transcriptional repressor (MtrR) and three proteins (MtrC-MtrD-MtrE) that form a multidrug efflux pump known to export macrolides. Strong regions of linkage disequilibrium mapped to the overlapping mtrR and mtrCDE promoters and mtrD. Genetic analyses revealed that these mosaic-like sequences increased transcription of mtrCDE and MtrD function, respectively. These changes also had strong epistatic effects that collectively were responsible for decreased susceptibility to MtrCDE substrates, including Azi. The report emphasizes the importance of gene exchange among neisserial species and development of antibiotic resistance in gonococci, both of which have ramifications for detection of resistance markers and efficacy of antibiotic treatment regimens for gonorrhea.

Keywords: Neisseria gonorrhoeae; antibiotic resistance; gonorrhea; transformation.

FIG 1

(A) Shown is the mtr locus of N. gonorrhoeae with horizontal lines above regions of strong disequilibrium that resulted from gonococcal recombination of DNA from N. lactamica or N. meningitidis and bent arrows showing sites of initiation of transcription. Examples of the likely impact of mosaic-like sequences within the mtrR and mtrD regions are noted above the horizontal lines. (B) The overlapping mtrR and mtrCDE promoters in N. gonorrhoeae nonmosaic strain FA19 are shown. The red-highlighted T:A base pair is representative of a site for the 1-bp deletion in many gonococcal strains displaying high levels of expression of mtrCDE and loss of mtrR expression (3). The adjacent green T:A base pair represents a nucleotide change within the mtrR or mtrCDE promoter that may impact mtrR or mtrCDE transcription as part of the mosaic-like sequence that can be generated by recombination. (C) The MtrC-MtrD-MtrE pump, showing the position of MtrD in the inner membrane (IM), MtrC in the periplasmic space (PS), and MtrE in the outer membrane (OM).