Naturally-Occurring Polymorphisms in QcrB Are Responsible for Resistance to Telacebec in Mycobacterium abscessus

Abstract

Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacteria that is quickly emerging as a global health concern. M. abscessus pulmonary infections are frequently intractable due to the high intrinsic resistance to most antibiotics. Therefore, there is an urgent need to discover effective pharmacological options for M. abscessus infections. In this study, the potency of the anti-tuberculosis drug Telacebec (Q203) was evaluated against M. abscessus. Q203 is a clinical-stage drug candidate targeting the sub-unit QcrB of the cytochrome bc1:aa3 terminal oxidase. We demonstrated that the presence of four naturally-occurring polymorphisms in the M. abscessus QcrB are responsible for the high resistance of the bacterium to Q203. Genetics reversion of the four polymorphism sensitized M. abscessus to Q203. While this study highlights the limitation of a direct drug repurposing approach of Q203 and related drugs for M. abscessus infections, it reveals that the M. abscessus cytochrome bc1:aa3 respiratory branch is sensitive to chemical inhibition.

Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII2CIV2 Supercomplex Binding, and In Vitro Antimycobacterial Activity

“…Therefore, other yet unknown mechanisms must be the reason for the insensitivity of M. abscessus to Q203 . In addition, PK parameters such as solubility, permeation through human and bacterial cell membranes, and bacterial metabolism of the IPAs could play a role in limiting or preventing growth inhibitory activity.…”

Uncovering interactions between mycobacterial respiratory complexes to target drug-resistant Mycobacterium tuberculosis

“…Interestingly, in Mycobacterium ulcerans, which has a non-functional Cyt-bd and relies exclusively on Cyt-bccaa 3 as a terminal oxidase, inhibitors of Cyt-bccaa 3 are bactericidal (Scherr et al, 2018;Liu et al, 2019). Alternatively, naturally occurring polymorphisms in the Cyt-bccaa 3 of Mycobacterium abscessus provide a high level of resistance to Q203 (Sorayah et al, 2019). Combined, this data demonstrates that starving M. tuberculosis, and potentially other mycobacterial species, of their ability to use oxygen as a terminal electron acceptor can result in bactericidal outcomes and is a vulnerable target for drug discovery (Bajeli et al, 2020;Lee B. S. et al, 2020;Sviriaeva et al, 2020).…”

Pipeline of anti‐Mycobacterium abscessus small molecules: Repurposable drugs and promising novel chemical entities

“…This compound targets the QcrB subunit of the cytochrome bc1:aa3 , one of the two terminal oxidases produced by most mycobacteria 74 . Disappointingly, and despite QcrB being a target of therapeutic interest in M. abscessus as in other mycobacteria, Q203 completely lacks activity against this species due to polymorphisms in QcrB 75 . Despite their demonstrated efficacy, a concern with bedaquiline and Q203 is the observation that they tend to suppress the ATP burst normally observed upon treatment mycobacteria with cell wall inhibitors (and some other drugs), thereby diminishing the bactericidal potency of a number of antibiotics used in combination 76,77 .…”