Novel targets and inhibitors of the Mycobacterium tuberculosis cytochrome bd oxidase to foster anti-tuberculosis drug discovery

ABSTRACT

Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the most devastating bacterial disease. Multidrug-resistant Mtb strains are spreading worldwide, underscoring the need for new anti-TB targets and inhibitors. The respiratory chain complexes, including the cytochrome bd oxidase (cyt-bd), have been identified as an attractive target for drug development. Recent novel structural and mechanistic insight as well as inhibitors of Mtb’s cyt-bd brought this enzyme into the focus.

Areas covered

In this review, the authors describe conditions that stimulate the biogenesis of Mtb cyt-bd, its structural-, mechanistic-, and substrate-binding traits. They discuss the present Mtb cyt-bd inhibitors, novel targets within the enzyme and structure activity relationship features that are required for mycobacterial cyt-bd inhibition and augment their understanding on improving the potency of cyt-bd inhibitors.

Expert opinion

A deeper structure-mechanistic understanding of Mtb’s cyt-bd is a prerequisite for in silico efforts to: (i) identify pathogen specific targets for the design of novel nontoxic hit molecules, forming the platform for the development of new leads, (ii) design mechanism of action studies, (iii) perform medicinal chemistry of existing inhibitors to improve their potency and pharmacokinetic/-dynamic properties. Phase studies with such optimized cyt-bd inhibitors in combination with anti-TB compounds targeting the oxidative phosphorylation pathway is recommended.

KEYWORDS:

• Cytochrome bd oxidase
• virulence
• oxidase
• Mycobacteria
• Tuberculosis
• Telacebec
• dual inhibition
• multi-drug resistance

Article highlights

• One of the key adaptations of mycobacteria in response to adverse growth condition is to recalibrate its energy needs by turning on the cyt-bd oxidase with high oxygen affinity and to use specific electron carriers.

• Elucidation of structural and mechanistic details of the mycobacterial cyt-bd oxidase further augments our understanding of Mtb cyt-bd oxidase functioning, essential for future compound design.

• Cyt-bd inhibitors with a N-aryl crosslinked group display good anti-TB potency.

• Pharmacological inhibition of cyt-bd together with Telacebec or BDQ have mirrored the knock down effects of cyt-bd oxidase. The cyt-bd inhibitor not only in combination with Telacebec, but also with BDQ have been shown to exert synergistic actions in enhancing the potency of the drug combination.

• Recently characterized cyt-bd ligands might need further optimization of their pharmacokinetic properties to improve in vivo potency of ligands. This enables further translation of such optimized lead inhibitor(s) into novel drug combination regimen with mechanistically coupled anti-TB drugs.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

SUPPLEMENTARY MATERIAL

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17460441.2023.2224553

Additional information

Funding

The authors are supported by the National Research Foundation (NRF) Singapore, through the NRF Competitive Research Programme (CRP), Grant Award Number NRF-CRP27-2021-0002.