WhiB7, a transcriptional activator that coordinates physiology with intrinsic drug resistance in Mycobacterium tuberculosis

Abstract

Current tuberculosis treatment regimens are notoriously limited, lengthy and becoming increasingly ineffective due to the emergence of drug-resistant mutant strains of Mycobacterium tuberculosis. The intrinsic resistance of M. tuberculosis to the majority of available drugs relies both on the impermeability of its cell envelope, and its ability to activate specific genes and physiological states. WhiB7 is a transcriptional regulatory protein underlying this adaptive process. Transcription of the whiB7 gene is upregulated in response to a variety of antibiotics having different structures and targets, as well as in response to metabolic signals. The whiB7 regulon activates various systems of intrinsic drug resistance involving antibiotic export, antibiotic inactivation (by chemical modifications of the drug or its target) and significant changes to thiol redox balance. Drugs have been identified that inactivate resistance determinants in the whiB7 regulon, thereby potentiating the activities of diverse antibiotics against M. tuberculosis.

Keywords::

• antibiotic resistance
• combinational therapy
• Mycobacterium tuberculosis
• redox
• tuberculosis
• WhiB

Acknowledgements

The authors would like to thank Kien Nguyen and Gaye Sweet for their constructive comments on the review. J Burian and CJ Thompson wrote the review; S Ramón-García made important contributions in developing concepts; CG Howes contributed data analysis.

Financial & competing interests disclosure

This work was supported by grants from the Canadian Institute of Health Research (MOP-82855) and the Canadian Lung Association. 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.

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