Targeting Type VII/ESX Secretion Systems for Development of Novel Antimycobacterial Drugs

Nov 20, 2013Current pharmaceutical design

Targeting type VII secretion systems to develop new drugs against mycobacteria

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Abstract

The genome of Mycobacterium tuberculosis encodes 5 type VII secretion systems, with some being essential for viability and virulence.

Type VII secretion systems (T7SS) play a crucial role in the biology and pathogenicity of M. tuberculosis.
Three of the five identified T7SS (ESX-1, ESX-3, ESX-5) are essential for the bacterium's survival or ability to cause disease.
ESX-1 and ESX-5 are particularly associated with the virulence of M. tuberculosis.
T7SS/ESX systems represent potential targets for the development of new anti-tuberculosis drugs.
Current knowledge suggests that targeting T7SS/ESX could improve treatment strategies against drug-resistant strains of M. tuberculosis.

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The emergence of multi- and extensively-drug resistant strains of Mycobacterium tuberculosis makes the development of novel anti-tubercular compounds and the identification of alternative mycobacterial drugable targets urgent priorities. Recently, type VII secretion systems (T7SS) have been discovered in mycobacteria. The genome of M. tuberculosis encodes 5 of such systems (ESX-1 to -5), three of which have been characterized and shown to be essential for viability (ESX-3, ESX-5) or virulence (ESX-1, ESX-5). Because of their crucial role in host-pathogen interactions as well as their involvement in basic biological processes of tubercle bacilli, T7SS/ESX represent promising targets for novel anti-tuberculosis drugs. Here, we review the current knowledge of the T7SS/ESX and their impact on M. tuberculosis physiology and virulence. Finally, we discuss the possible approaches to develop T7SS/ESX inhibitors.

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