Unprecedented in vivo activity of telacebec against Mycobacterium leprae
Abstract
Background
Leprosy, a chronic infectious disease caused by *Mycobacterium leprae*, continues to pose significant public health challenges globally, particularly in endemic regions. Current multi-drug therapy (MDT), while largely effective, is prolonged and can be associated with side effects and issues of patient adherence, highlighting the continuous need for novel, more efficacious, and shorter treatment regimens. In this ongoing quest, new drug candidates that specifically target the electron transport chain (ETC) of *M. leprae* are emerging as a highly promising advance in the development of next-generation leprosy treatments. The ETC is a fundamental metabolic pathway essential for bacterial survival, making it an attractive target for antimicrobial intervention. In the present study, we embarked on a comprehensive evaluation of the bactericidal activity of telacebec (TCB), a novel drug candidate currently in Phase 2 clinical trials for tuberculosis. Our investigation meticulously assessed TCB’s efficacy both as a monotherapy and in combination with two other well-known ETC-targeting antibiotics, bedaquiline (BDQ) and clofazimine (CFZ), to determine their potential for enhancing leprosy treatment outcomes.
Methodology/Principal Findings
To rigorously assess the bactericidal activity of the tested drugs, we employed the established and highly reproducible reference leprosy proportional bactericidal mouse footpad model. This animal model is widely recognized for its ability to accurately mimic *M. leprae* infection dynamics and therapeutic responses *in vivo*. A total of 410 mice were carefully allocated into various experimental groups. For the untreated control group and groups designated for drug monotherapies, mice were inoculated in their footpads with *M. leprae* strain THAI53 at bacillary concentrations ranging from 5×10^4 to 5×10^0. For groups evaluating drug combinations, the inoculum concentrations ranged from 5×10^4 to 5×10^1 bacilli, ensuring a suitable challenge for assessing combined therapeutic effects. Mice were then randomly assigned to one of two control groups or seven test groups. The control groups included an untreated group, which served as a baseline for *M. leprae* growth, and a group receiving standard multi-drug therapy (MDT), comprising rifampin, dapsone, and clofazimine, administered at doses equipotent to human therapeutic dosing. The seven test groups were constituted as follows: TCB at 10mg/kg, bedaquiline (BDQ) at 25mg/kg, clofazimine (CFZ) at 20mg/kg, a combination of CFZ + BDQ, TCB + BDQ, TCB + CFZ, and a triple combination of TCB + CFZ + BDQ. Mice in the MDT group received a one-month treatment regimen, while those in the TCB, RIF, BDQ, and CFZ monotherapy or combination groups received only a single dose of the respective drugs. Twelve months post-treatment, all mice were humanely sacrificed, and the *M. leprae* bacilli in their footpads were meticulously enumerated. This extended observation period allowed sufficient time to assess long-term bactericidal effects and prevent relapse. The results were highly encouraging: all footpads in the MDT group, the TCB monotherapy group, and all combination therapy groups (except for one specific combination) became entirely negative for *M. leprae* bacilli. The sole exception was the TCB + CFZ combination group, where two mice still exhibited positive footpads at the 5×10^4 inoculum concentration, indicating a potential issue with this particular pairing.
Conclusion
Our study unequivocally demonstrated that monotherapy with telacebec exhibited robust and significant bactericidal activity against *M. leprae*, a level of efficacy comparable to that achieved with the established standard multi-drug therapy. Furthermore, the evaluation of various combination therapies revealed that nearly all tested combinations were as effective as MDT in eradicating the leprosy bacilli. This underscores the potential of incorporating TCB into future, potentially shorter, treatment regimens. However, a noteworthy and critical finding emerged regarding the combination of TCB and clofazimine, which proved to be an exception. Unlike other combinations, TCB + CFZ did not achieve complete sterilization of the footpads in all instances, as evidenced by the persistence of bacilli in a subset of mice. This observation strongly suggests a possible antagonistic interaction between these two drugs, telacebec and clofazimine, which warrants further in-depth investigation to understand the underlying pharmacological mechanisms. These findings have important implications for optimizing drug combinations in future leprosy treatment protocols.
Copyright: © 2025 Chauffour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Conflict of Interest Statement
We have meticulously reviewed the journal’s policy regarding conflicts of interest, and the authors of this manuscript wish to declare the following: A.C., N.V., and A.A. are actively involved as participants in the Respiri-TB project, a collaborative initiative undertaken in partnership with Janssen Pharmaceutica. Conversely, V.J. and K.P. have explicitly stated that no competing interests exist in relation to this work.