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Repurposing clinically approved antibacterial drugs for treponematoses therapy

Project description

Evaluation of antibacterial treatment options for treponematoses therapy

Current therapeutic options for human treponematoses (syphilis, yaws, pinta) are generally restricted to injectable penicillin. Yaws is treatable with azithromycin, but there is a real risk of dissemination of the macrolide-resistant strains. The drug susceptibility profile of Treponema pallidum (T.p.) is unknown because the microorganism could not be grown in culture. Penicillin treatment failure is usually related to syphilis bacteria surviving in the central nervous system (CNS). The EU-funded Trep-AB project proposes evaluation of approved antibacterial treatment options with good CNS penetration that could be efficacious for all stages of T.p. infection. Preliminary study identified several candidate antibiotics using computational prediction of drug activity against T.p. and other spirochetes. Researchers will test 20 potential drug candidates in the recently developed T.p. specific culture methods of drug susceptibility. The results will be confirmed in an experimental rabbit model of infection and if successful, translated into clinical trials.

Objective

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.

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Coordinator

FUNDACION FLS DE LUCHA CONTRA ELSIDA LAS ENFERMEDADES INFECCIOSASY LA PROMOCION DE LA SALUD Y LACIENCIA
Net EU contribution
€ 1 150 678,81
Address
Carretera de canyet hospital germans trias i pujol planta 2
08916 Badalona
Spain

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Region
Este Cataluña Barcelona
Activity type
Research Organisations
Links
Other funding
€ 0,00

Beneficiaries (2)