Shared Characteristics Between Mycobacterium tuberculosis and Fungi Contribute to Virulence

Sam Willcocks; Brendan W Wren

Disclosures

Future Microbiol. 2014;9(5):657-668. 

In This Article

Metabolic Similarities & Drug Targets

Identification of targets that may be prevalent among fungi but exceptional in non-mycobacterial prokaryotes may yield potential avenues for novel therapies. Examples of the potential for anti-fungal agents to be used against M. tuberculosis may be found in the azole class of drugs that target cytochrome P450 enzymes. These enzymes are ubiquitous in eukaryotes but rare in bacteria, yet M. tuberculosis expresses a large number and is therefore susceptible to azole antifungals.[96,97] Potential targets for pharmacological intervention have also been identified in the field of metabolomics. The paucity of available glucose in the intracellular environment is circumvented by M. tuberculosis through its use of the glyoxylate cycle, enabling the use of alternative carbon sources for energy and contributing to virulence. The glyoxylate cycle is not available to most bacterial species,[98] but genomic microarray analysis has revealed that it is used by both S. cerevisiae and C. albicans post-phagocytosis.[99] In addition, M. tuberculosis possesses key enzymes that can function similarly to both isocytrate lyase in the glyoxylate cycle and 2-methylcitrate lyase in the methylcitrate cycle. Most bacteria have dedicated enzymes for these reactions, rather than having enzymes with dual activity in both cycles. This characteristic has only previously been reported in Candida lipolytica, Saccharomyces cerevisiae and Aspergillus nidulans.[100]

There are further comparisons that can be made between fungi and mycobacteria, such as their shared ability to metabolize particular amino acids and their ability to sequester host iron to aid persistence and virulence. Rv1347c is a virulence factor of M. tuberculosis involved in the biosynthesis of an iron-binding siderophore; it has no ortholog among non-actinomycetes, but has high amino acid sequence homology with that of Ustilago maydis, a pathogenic smut fungus. Both may have derived from a common protein ancestor shared with SidL, a protein in A. fumigatus that is essential for growth in iron-poor conditions.[101]

While several bacterial species have been noted to metabolize cholesterol, M. tuberculosis encodes a transport system specifically for the import of exogenous host cholesterol that is essential for virulence.[102] These genes are located at the mce4 locus, and while there is no amino acid sequence similarity among fungi, A. fumigatus has evolved its own cholesterol import mechanism to similarly support its growth; this is indicative of independently evolved solutions to a common problem, namely access to a carbon source inside the host. This quality of A. fumigatus has been suggested as a reason for the antifungal activity of sterol biosynthesis inhibitors,[103] and is an avenue that may allow for similar exploitation in anti-tuberculosis drug research.

A dual approach of developing antimycobacterial and antifungal agents should have considerable added value. Expanding the search for novel antimycobacterial strategies to consider characteristics shared with fungi is surely of value in the era of XDR-TB.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....