A large screen identifies beta-lactam antibiotics which can be repurposed to target the syphilis agent

Syphilis, caused by the spirochete Treponema pallidum subsp. pallidum (hereafter called T. pallidum), is re-emerging as a worldwide sexually transmitted infection. A single intramuscular dose of benzathine penicillin G is the preferred syphilis treatment option. Both supply shortage concerns and the potential for acquired antibiotic resistance further the need to broaden the repertoire of syphilis therapeutics. We reasoned that other β-lactams may be equally or more effective at targeting the disease-causing agent, Treponema pallidum, but have yet to be discovered due to a previous lack of a continuous in vitro culture system. Recent technical advances with respect to in vitro T. pallidum propagation allowed us to conduct a high-throughput screen of almost 100 β-lactams. Using several molecular and cellular approaches that we developed or adapted, we identified and confirmed the efficacy of several β-lactams that were similar to or outperformed the current standard, benzathine penicillin G. These options are either currently used to treat bacterial infections or are synthetic derivatives of naturally occurring compounds. Our studies not only identified additional potential therapeutics in the resolution of syphilis, but provide techniques to study the complex biology of T. pallidum— a spirochete that has plagued human health for centuries.