Repurposing clinically approved antibacterial drugs for treponematoses therapy

ended

Current therapeutic options for human treponematoses, syphilis and yaws, are, broadly speaking, restricted to one antibiotic: injectable penicillin. The drug susceptibility profile of Treponema pallidum (T.p) is unknown because the microorganism could not be grown in culture. Treatment failure after penicillin has been related to syphilis bacteria that survive in the central nervous system (CNS) and the potential of strains to acquire resistance to penicillin has recently been recognized. Yaws can be treated with azithromycin but there is a real risk that macrolide-resistant strains disseminate widely and jeopardize the global eradication campaign. I propose a research program to have other validated treatment options with good CNS penetration that are efficacious for all the stages of treponemal infection. Our preliminary results using computational prediction of drug activity based on similarity to drugs with known activity against T.p. and other spirochetes shows several candidate antibiotics. I will take advantage of recent developments in culture methods for determination of drug susceptibility to test 20 prioritized drugs. These results will be confirmed in experimentally infected rabbits treated with the investigational drugs and assessed for lesion development and T.p. burden. My second approach will exploit the established expertise of my team conducting randomized clinical trials to evaluate the efficacy of the 2 most promising candidates compared to standard treatment to cure patients with syphilis/yaws. Such studies will incorporate in-depth studies of recurrent events among study participants, to further clarify the biological basis and identify mutations that confer resistance to B-lactams. New antibacterial oral drugs for the treatment of treponematoses will be a tremendous resource in case of penicillin treatment-failure, resistance, shortage, allergy, or for use in yaws combination regimens to reduce the likelihood of resistance selection.