Prioritizing Genomic Drug Targets in Pathogens: Application to Mycobacterium tuberculosis

Abstract

We have developed a software program that weights and integrates specific properties on the genes in a pathogen so that they may be ranked as drug targets. We applied this software to produce three prioritized drug target lists for Mycobacterium tuberculosis, the causative agent of tuberculosis, a disease for which a new drug is desperately needed. Each list is based on an individual criterion. The first list prioritizes metabolic drug targets by the uniqueness of their roles in the M. tuberculosis metabolome (“metabolic chokepoints”) and their similarity to known “druggable” protein classes (i.e., classes whose activity has previously been shown to be modulated by binding a small molecule). The second list prioritizes targets that would specifically impair M. tuberculosis, by weighting heavily those that are closely conserved within the Actinobacteria class but lack close homology to the host and gut flora. M. tuberculosis can survive asymptomatically in its host for many years by adapting to a dormant state referred to as “persistence.” The final list aims to prioritize potential targets involved in maintaining persistence in M. tuberculosis. The rankings of current, candidate, and proposed drug targets are highlighted with respect to these lists. Some features were found to be more accurate than others in prioritizing studied targets. It can also be shown that targets can be prioritized by using evolutionary programming to optimize the weights of each desired property. We demonstrate this approach in prioritizing persistence targets.

The Non-mevalonate Pathway of Isoprenoid Precursor Biosynthesis

“…The DOXP pathway is absent from humans and occurs in serious human pathogens, and component enzymes have been validated genetically as drug targets (44 -46). 3 Enzymes such as these are particularly valued for drug development because they uniquely consume a substrate or generate a specific product, and their function cannot be compensated for by another enzyme (47).…”

Protein targets for structure-based anti-Mycobacterium tuberculosis drug discovery

“…Impaired function of ATP synthase may lead to ATP depletion and imbalance in pH homeostasis, both causing decreased survival (Deckers-Hebestreit and Altendorf, 1996;Hasan et al, 2006). Recently, an ATP synthase inhibitor (R207910), which targets F0 subunit of ATP synthase, atpE, was reported to contain high potency on suppressing both drug-sensitive and drug-resistant M. tuberculosis in vitro (Andries et al, 2005).…”

Identifying Vulnerable Pathways in Mycobacterium tuberculosis by Using a Knockdown Approach

“…Novel drug targets are required for tuberculosis; essentiality is a common first step in validating a target, but there is increasing interest in identifying vulnerable targets for which incomplete inhibition effects a lethal phenotype (1,7,10). We utilized the tetracycline-inducible system to generate knockdown strains of a number of genes/operons in Mycobacterium tuberculosis to determine essentiality and vulnerability simultaneously.…”