Mycothiol: a target for potentiation of rifampin and other antibiotics against Mycobacterium tuberculosis

Abstract

Actinomycetes, including Mycobacterium species, are Gram-positive bacteria that use the small molecule mycothiol (MSH) as their primary reducing agent and in the detoxification of xenobiotics. Due to these important functions, MSH is a potential target for the development of antibiotics for the treatment of tuberculosis. This review summarizes the progress to date on the viability of enzymes involved in MSH biosynthesis and MSH-dependent detoxification as drug targets, biochemical characterization of target enzymes (structure, mechanism and substrate specificity) and development of MSH biosynthesis and MSH-dependent detoxification enzyme inhibitors. In addition, the ability of MSH to influence the sensitivity of mycobacteria to existing antibiotics and potential of MSH biosynthesis and MSH-dependent detoxification enzyme inhibitors to modulate the activity of existing antibiotics are described.

Keywords::

• isoniazid
• MshA
• MshB
• MshC
• MshD
• mycothiol
• mycothiol-conjugate amidase
• mycothiol-S-transferase
• mycothione reductase
• rifampin
• TB

Acknowledgements

Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (CA, USA; supported by NIH P41 RR001081).

Financial & competing interests disclosure

The author has 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.

No writing assistance was utilized in the production of this manuscript.