Plasmids in Neisseria gonorrhoeae: drivers of DoxyPEP failure and an emerging threat for current therapy.

SUMMARYGonococcal disease is a serious threat to reproductive health, with cases and antimicrobial resistance steadily increasing. Currently, the β-lactam antibiotic ceftriaxone is the mainstay of treatment, while doxycycline post-exposure prophylaxis (DoxyPEP) is being implemented to reduce bacterial sexually transmitted infections. Neisseria gonorrhoeae, the causative agent of gonorrhoea, can harbor two resistance plasmids, pbla and pConj, which confer resistance to penicillin and tetracycline/doxycycline, respectively. Additionally, over 90% of isolates carry a small plasmid, pCryp, whose function remains unclear. Of concern, pbla-encoded β-lactamases only differ from extended-spectrum β-lactamases by one or two amino acid changes. DoxyPEP is completely ineffective against isolates carrying pConj expressing tetM. tetM-mediated resistance has increased in the gonococcus following introduction of DoxyPEP and is widespread in low- and middle-income countries. Therefore, plasmids pose a significant risk to the successful management of gonococcal infection. Here, we review current knowledge of the epidemiology and biology of gonococcal plasmids. We describe the hierarchy of acquisition and dependencies between plasmids in N. gonorrhoeae and their subsequent evolution, transfer dynamics, fitness costs, and benefits to provide a better understanding of the implications of the plasmids on public health interventions for controlling and treating gonococcal infection.