New therapeutic strategies for Mycobacterium abscessus pulmonary diseases – untapping the mycolic acid pathway

ABSTRACT

Introduction

Treatment options against Mycobacterium abscessus infections are very limited. New compounds are needed to cure M. abscessus pulmonary diseases. While the mycolic acid biosynthetic pathway has been largely exploited for the treatment of tuberculosis, this metabolic process has been overlooked in M. abscessus, although it offers many potential drug targets for the treatment of this opportunistic pathogen.

Areas covered

Herein, the authors review the role of the MmpL3 membrane protein and the enoyl-ACP reductase InhA involved in the transport and synthesis of mycolic acids, respectively. They discuss their importance as two major vulnerable drug targets in M. abscessus and report the activity of MmpL3 and InhA inhibitors. In particular, they focus on NITD−916, a direct InhA inhibitor against M. abscessus, particularly warranted in the context of multidrug resistance.

Expert opinion

There is an increasing body of evidence validating the mycolic acid pathway as an attractive drug target to be further exploited for M. abscessus lung disease treatments. The NITD−916 studies provide a proof-of-concept that direct inhibitors of InhA are efficient in vitro, in macrophages and in zebrafish. Future work is now required to improve the activity and pharmacological properties of these inhibitors and their evaluation in pre-clinical models.

KEYWORDS:

• Chemotherapy
• InhA
• Inhibition
• MmpL3
• Mycobacterium abscessus
• Mycolic acid

Article highlights

• Mycobacterium abscessus lung disease is a highly drug-resistant bacterial infection with very limited treatment options.

• The need to accelerate and improve novel antibiotics and regimens for M. abscessus pulmonary infections is urgent.

• The M. abscessus drug discovery pipeline is currently underpopulated and needs to be filled.

• The mycolic acid biosynthesis pathway, containing potential attractive drug targets, has recently been investigated for the search of new effective compounds against M. abscessus.

• Hit compounds against InhA and MmpL3, involved in the synthesis and transport of mycolic acids, are active against M. abscessus.

• The set of hit compounds identified encourages further hit-to-lead development to improve efficacy and pharmacokinetic properties.

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.

Reviewers disclosure

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

Author contribution

All authors substantially contributed to the conception and design of the review article and interpreting the relevant literature and were involved in the writing the review article or revised it for intellectual content.

Additional information

Funding

We acknowledge the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation for funding the PhD of MA and the “Equipe FRM EQU202103012588” funding to LK. This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No: HHSN272201700059C.