Mycobacterium Tuberculosis Evolutionary Pathogenesis and its Putative Impact on Drug Development

Fabien Le Chevalier; Alessandro Cascioferro; Laleh Majlessi; Jean Louis Herrmann; Roland Brosch

Disclosures

Future Microbiol. 2014;9(8):969-985. 

In This Article

Mycobacterial Secretion Systems & Their Potential Utility as Drug Targets

Screening of different classes of compounds with antitubercular activity combined with sequence analysis and recombineering has revealed some new potential drug targets of M. tuberculosis, such as the membrane protein EccB3, which represents a novel candidate not targeted by currently existing anti-TB drugs.[59] The EccB3 protein is a conserved component of the ESX-3 secretion system, which represents one of the five type VII secretion systems of M. tuberculosis.[60] In contrast to ESX-1, which is not essential for in vitro growth of M. tuberculosis but is necessary for multiplication and survival of M. tuberculosis in the host cell,[61] ESX-3 is a secretion system whose genes are essential for the in vitro growth of M. tuberculosis in standard culture media[31] due to their role in mycobactin-mediated iron acquisition and zinc uptake.[62,63] The aforementioned finding that the ESX-3 system can be targeted by small-compound inhibitors is an encouragement for further research and the development of inhibitors that might inactivate components of the secretion systems of M. tuberculosis. Apart from the ESX-3 system, among the type VII secretion systems, there is also the ESX-5 system, which has recently been shown to contain genes (e.g., eccC5 ) that are essential for the in vitro growth of M. tuberculosis,[31,64] in addition to genes that are involved in the virulence and export of PE/PPE antigens (Figure 3).[65,66]

Figure 3.

Working model of two selected secretion pathways (twin-arginine translocation and ESX) that are thought to be involved in the pathogenicity of Mycobacterium tuberculosis . (A) The genomic loci of two of the five ESX systems (ESX-1 and ESX-5), as well as the components of the TAT system. The gene nomenclature corresponds to that of the reference strain Mycobacterium tuberculosis H37Rv. (B) A model of the cell envelope of M. tuberculosis with the putative locations of selected proteins from the TAT and the ESX systems.
The exact shape and mechanism by which the proteins are transported through the outer membrane is still unknown.
RR: Twin arginine; TAT: Twin-arginine translocation.
(A) Data taken from [11,60,64,67]; (B) Data taken from [60,67].

Besides the type VII secretion systems, which represent specialized secretion systems of mycobacteria and related actinobacteria, M. tuberculosis also uses various other secretion pathways for protein export[67] (i.e., the SecA1-mediated general secretory pathway,[68] the alternative SecA2-operated pathway[69] and a twin-arginine translocation (TAT) system[70,71]), which might also serve as targets for new drugs.[72] The mycobacterial TAT system, for example, is constituted by a protein complex that includes TatA (Rv2094c) and TatC (Rv2093c), which are essential for the in vitro growth of M. tuberculosis[29,31,71] and are thought to be localized in the plasma membrane (Figure 3). A third protein called TatB (Rv1224), which is encoded elsewhere in the genome, also seems to be essential for the function of the TAT apparatus in M. tuberculosis,[71] although in TAT systems of other bacterial species, this does not always seem to be the case.[73] Finally, based on sequence homology, a fourth protein, TatD (Rv1008), a nonessential protein with supposed DNase activity, is also a putative component of the TAT protein export system in M. tuberculosis. The proteins secreted by the TAT system are characterized by the presence of the twin arginine (RR) motif in the N-terminal signal sequence.[71,73,74] In contrast to other secretion pathways of M. tuberculosis, the TAT system exports the proteins in their folded state. Among the various proteins with a TAT signal sequence motif, some have been described as being implicated in pathogenesis, such as the phospholipase C proteins (i.e., PlcA–D)[75] and resistance to β-lactam antibiotics, such as BlaC, representing a class A β-lactamase.[74]

Overall, it is clear that many of the proteins secreted by the various secretion pathways of M. tuberculosis play important roles in the survival and growth of the bacterium inside the host. Hence, specific protein export is a very important feature for pathogenic bacteria, as it enables the pathogen to withstand the defence mechanisms mounted by the host cells and/or exploit cellular functions for the benefit of the pathogen. Although the secreted proteins are often not essential for the in vitro growth of the organisms in culture broth, their in vivo growth essentiality might be exploited as an in vivo drug target for chemical compounds that could target these proteins during infection. As such, research on the potential virulence factors of pathogenic mycobacteria combined with elucidating their mechanisms of action might uncover new, unconventional targets for the development of new classes of antimycobacterial compounds that might act under in vivo conditions in synergy with more conventional bactericidal drugs.

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