Origin, evolution, and success of pbla, 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 doxycycline post-exposure prophylaxis (Doxy-PEP). Here, we investigated the origin and evolution of the beta-lactamase plasmid, pbla. We demonstrate that pbla was likely acquired by the gonococcus from Haemophilus ducreyi, and describe the subsequent evolutionary pathways taken by the three major pbla variants. We show that the ability of pConj to spread pbla promotes their co-occurrence in the gonococcal population and the spread of pbla. Changes that mitigate fitness costs of pbla and the emergence of TEM beta-lactamases that 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 both plasmids, strains which carry pConj and are resistant against third generation cephalosporins, and the emergence of plasmid-mediated ESBL in the gonococcus, with significant public health consequences.