Emerging opportunities of exploiting mycobacterial electron transport chain pathway for drug-resistant tuberculosis drug discovery

ABSTRACT

Introduction: Tuberculosis (TB) is a leading infectious disease worldwide whose chemotherapy is challenged by the continued rise of drug resistance. This epidemic urges the need to discover anti-TB drugs with novel modes of action.

Areas covered: The mycobacterial electron transport chain (ETC) pathway represents a hub of anti-TB drug targets. Herein, the authors highlight the various targets within the mycobacterial ETC and highlight some of the promising ETC-targeted drugs and clinical candidates that have been discovered or repurposed. Furthermore, recent breakthroughs in the availability of X-ray and/or cryo-EM structures of some targets are discussed, and various opportunities of exploiting these structures for the discovery of new anti-TB drugs are emphasized.

Expert opinion: The drug discovery efforts targeting the ETC pathway have led to the FDA approval of bedaquiline, a F_OF₁-ATP synthase inhibitor, and the discovery of Q203, a clinical candidate drug targeting the mycobacterial cytochrome bcc-aa3 supercomplex. Moreover, clofazimine, a proposed prodrug competing with menaquinone for its reduction by mycobacterial NADH dehydrogenase 2, has been repurposed for TB treatment. Recently available structures of the mycobacterial ATP synthase C9 rotary ring and the cytochrome bcc-aa3 supercomplex represent further opportunities for the structure-based drug design (SBDD) of the next-generation of inhibitors against Mycobacterium tuberculosis.

KEYWORDS:

• Tuberculosis
• ATP synthase
• cytochrome bcc inhibitor
• multi-drug resistance
• mycobacterium

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Article Highlights

• TB chemotherapy is challenged by the multi-drug resistance and extended duration of treatment.

• Mycobacterium tuberculosis (Mtb) electron transport chain pathway represents a hub of multiple anti-TB drug targets.

• Mtb F_OF₁-ATP synthase, cytochrome bcc-aa3 supercomplex and NDH-2 are established targets for the existing drugs.

• Mtb SDH-1 and cytochrome bd oxidase are unattended drug targets that urge an attention for exploitation to identify new anti-TB agents.

• Structure-based drug design may play a vital role in identifying new scaffolds or redesigning the existing scaffolds using the recently available structures of Mtb ATP synthase and cytochrome bcc-aa3 supercomplex.

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Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

One referee is an employee of Hackensack Meridian Health Inc. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.