Synergistic Effect of Q203 Combined with PBTZ169 against Mycobacterium tuberculosis

Abstract

Q203 is a first-in-class drug candidate against Mycobacterium tuberculosis. In its recently completed phase 2 clinical trial, Q203 reduced the number of live M. tuberculosis cells in a dose-dependent manner. This orally active small molecule blocks M. tuberculosis growth by inhibiting the cytochrome bc(1) complex, which consequently inhibits the synthesis of ATP. Here, we studied the interaction profiles of Q203 with several antituberculosis drugs or drug candidates (specifically, bedaquiline, PBTZ169, PA-824, OPC-67683, SQ109, isoniazid, rifampin, streptomycin, and linezolid) using the checkerboard method, based on resazurin microtiter assays (REMAs). In the assay, none of the interactions between Q203 and the tested drugs were antagonistic, and most of the interactions were additive. However, the interaction between Q203 and PBTZ169 was synergistic, with a fractional inhibitory concentration index of 0.5. Furthermore, Q203 (one-half the MIC50) and PBTZ169 (one-half the MIC50) inhibited more bacterial growth on an agar plate compared to the dimethyl sulfoxide (DMSO) control. This synergistic effect was no longer effective when the Q203-PBTZ169 combination was tested against an M. tuberculosis mutant containing a T313A mutation causing resistance to Q203, suggesting that QcrB inhibition is integral to the Q203-PBTZ169 interaction. Thus, this synergy is not an off-target mechanism. Zebrafish (Danio rerio)-Mycobacterium marinum infection and a curing model further validated the synergistic effect of Q203 and PBTZ169 in vivo. In this study, the synergy between these two new antituberculosis drugs, Q203 and PBTZ169, is an important finding that could lead to the development of a new TB regimen.