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The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance

Novartis Institute for Tropical Diseases Pte Ltd, 10 Biopolis Road #05-01, Chromos, 138670, Singapore
Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Clinical Research Centre, 10 Medical Drive, 117597, Singapore
Author to whom correspondence should be addressed.
Current address: Public Health Research Institute, 225 Warren St, Newark, NJ 07103, USA.
Pharmaceuticals 2012, 5(11), 1210-1235;
Received: 27 August 2012 / Revised: 25 October 2012 / Accepted: 2 November 2012 / Published: 9 November 2012
(This article belongs to the Special Issue Antituberculosis Drugs)
In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may contribute to the development of phenotypic drug tolerance and induction of drug resistance. M. tuberculosis is intrinsically recalcitrant to small molecule permeation thanks to its thick lipid-rich cell wall. Passive diffusion appears to account for only a fraction of total drug permeation. As in other bacterial species, influx of hydrophilic compounds is facilitated by water-filled open channels, or porins, spanning the cell wall. However, the diversity and density of M. tuberculosis porins appears lower than in enterobacteria. Besides, physiological adaptations brought about by unfavorable conditions are thought to reduce the efficacy of porins. While intracellular accumulation of selected drug classes supports the existence of hypothesized active drug influx transporters, efflux pumps contribute to the drug resistant phenotype through their natural abundance and diversity, as well as their highly inducible expression. Modulation of efflux transporter expression has been observed in phagocytosed, non-replicating persistent and multi-drug resistant bacilli. Altogether, M. tuberculosis has evolved both intrinsic properties and acquired mechanisms to increase its level of tolerance towards xenobiotic substances, by preventing or minimizing their entry. Understanding these adaptation mechanisms is critical to counteract the natural mechanisms of defense against toxic compounds and develop new classes of chemotherapeutic agents that positively exploit the influx and efflux pathways of mycobacteria. View Full-Text
Keywords: Mycobacterium tuberculosis; drug transport; efflux; porins; resistance; persistence Mycobacterium tuberculosis; drug transport; efflux; porins; resistance; persistence
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Sarathy, J.P.; Dartois, V.; Lee, E.J.D. The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance. Pharmaceuticals 2012, 5, 1210-1235.

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