Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future

Abstract

Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae, including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor-made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection.

FIG 1

History of discovered and recommended antimicrobials and evolution of resistance in Neisseria gonorrhoeae, including the emergence of genetic resistance determinants, internationally. During the preantimicrobial era (before the 1930s), treatment consisted of, e.g., a healthier lifestyle, copaiba, cubebs, urethral irrigations, potassium permanganate, silver compounds, mercury compounds, and hyperthermia. SUL, sulfonamides; PEN, penicillin; SPT, spectinomycin; TET, tetracycline; CIP, ciprofloxacin; OFX, ofloxacin; CFM, cefixime; CRO, ceftriaxone; AZM, azithromycin; DOX, doxycycline.

FIG 2

Trans- and cis-acting regulatory elements that control expression of the mtrCDE efflux pump operon in Neisseria gonorrhoeae. Trans-acting elements behaving as repressors or genes that encode them are shown as barred lines (⊥), while those encoding activators are shown by arrows. The promoters responsible for transcription of mtrR and mtrCDE are shown with their respective −10 and −35 hexamer sequences (see bars over hexamers). Note that mtrR and mtrCDE are transcriptionally divergent, and only the mtrCDE coding strand is shown. The position of the 13-bp inverted repeat sequence (I.R.; AAAAAGACTTTTT) between the −10 and −35 hexamers of the mtrR promoter is shown within the 14 nucleotides in the dotted box, and a T nucleotide that is frequently deleted in strains that overexpress mtrCDE and exhibit a high level of resistance to pump substrates is shown in bold (329). The position of the new −10 hexamer sequence generated by a point mutation (C to T) that acts as a new promoter (mtr₁₂₀) for mtrCDE transcription (198) is shown. MtrR repression of mtrCDE is due to binding of two homodimers to the mtrCDE promoter, as shown by the barred line that extends to the region shown in the nucleotide sequence. MtrA binds upstream of the mtrCDE promoter (265). (Adapted from reference with permission.)