Efflux pump antibiotic binding site mutations are associated with azithromycin nonsusceptibility in clinicalNeisseria gonorrhoeaeisolates

Lyu and Moseng et al. used cryo-electron microscopy to characterize key residues involved in drug binding by mosaic-like MtrD efflux pump alleles in Neisseria gonorrhoeae (1). Isogenic experiments introducing key MtrD substitutions R714G and K823E increased macrolide MICs, leading the authors to predict that non-mosaic MtrD “gonococcal strains bearing both the mtrR promoter and amino acid changes at MtrD positions 714 or 823 could lead to clinically significant levels of Azi nonsusceptibility resistance”. We tested this hypothesis by analyzing a global meta-analysis collection of 4852 N. gonorrhoeae genomes (2). In support of their prediction, we identified clinical isolates with novel non-mosaic MtrD drug binding site substitutions across multiple genetic backgrounds associated with elevated azithromycin MICs (Table).