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Pharmaceuticals 2012, 5(11), 1210-1235; doi:10.3390/ph5111210
Review

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

1, 1,2,†,*  and 3
Received: 27 August 2012; in revised form: 25 October 2012 / Accepted: 2 November 2012 / Published: 9 November 2012
(This article belongs to the Special Issue Antituberculosis Drugs)
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Abstract: 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.
Keywords: Mycobacterium tuberculosis; drug transport; efflux; porins; resistance; persistence Mycobacterium tuberculosis; drug transport; efflux; porins; resistance; persistence
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

Sarathy JP, Dartois V, Lee EJD. The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance. Pharmaceuticals. 2012; 5(11):1210-1235.

Chicago/Turabian Style

Sarathy, Jansy P.; Dartois, Véronique; Lee, Edmund J.D. 2012. "The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance." Pharmaceuticals 5, no. 11: 1210-1235.



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