The origin and evolution of the gonococcal beta-lactamase plasmid, and implications for public health

Neisseria gonorrhoeae is a leading cause of sexually transmitted infection (STI) and a priority AMR pathogen. Two narrow host range plasmids, pbla and pConj, have contributed to ending penicillin and tetracycline therapy, respectively, and undermine current prevention strategies including Doxy-PEP. Here, we investigated the origin and evolution of the beta-lactamase plasmid, pbla. We show that the interplay between pbla and pConj influences their co-occurrence and the spread of pbla in the gonococcal population. We demonstrate that pbla was acquired by the gonococcus on at least two occasions from Haemophilus ducreyi, and describe the subsequent evolutionary pathways taken by the three major pbla variants. Changes that mitigate fitness costs of pbla and the emergence of TEM beta-lactamases which confer increased resistance have contributed to the success of pbla. In particular, TEM-135, which has arisen in certain pbla variants, increases resistance to beta-lactams and only requires one amino acid change to become an extended spectrum beta-lactamase (ESBL). The evolution of pbla underscores the threat of plasmid-mediated resistance to current therapeutic and preventive strategies against gonococcal infection. Given the close relationship between pbla and pConj, widespread use of Doxy-PEP is likely to promote spread of pConj and pbla, and emergence of plasmid-mediated ESBL in the gonococcus, with dire public health consequences.