PROBING THE INTRINSIC RESISTOME OF MYCOBACTERIUM TUBERCULOSIS MAPPING OF CHEMICAL SPACE: MODELING AND SIMULATION OF METABOLISM AND PREDICTIVE MODELS OF INFLUX AS FILTERS FOR DRUG-LIKE MOLECULES

Abstract

Tuberculosis (TB) is one of the most serious infectious diseases worldwide. Approximately one-third of the people are infected with Mycobacterium tuberculosis (Mtb), making tuberculosis (TB) one of the most prevalent infectious diseases in the world. Anti-tuberculosis (TB) drug resistance is a major public health problem that threatens progress made in TB care and control worldwide. Intrinsic resistance to antibiotics is posing severe threats to the treatments currently available for TB rendering them ineffective and incomplete. To deal with this scenario, efforts have to be directed towards mechanisms that are underexplored in the organism for the purpose of developing an effective and adequate treatment regime. Herein, we propose metabolic pathways of the mycobacterium as the choice of target for identifying and developing novel drug molecules that may act as potential inhibitors of the organism. In this study, we propose to explore the chemical space within Mtb to identify essential metabolites, and use this information to develop influx models for the organism. Mtb presents a plethora of molecular targets that hold a great potential for therapeutic intervention in the post genomic era. These opportunities present the Mtb genome as a highly druggable genome. Studies have identified proteins critical for the survival for M.tuberculosis that are likely to have high rates of success as drug candidates. Many of the druggable proteins are enzymes that control several metabolic processes within the cells by catalyzing the reactions converting nutrients into energy and new molecules which are in a way crucial for the survival of the microbe. Because metabolism is fundamental in sustaining microbial life, drugs that target pathogen-specific metabolites, enzymes and pathways can be very effective. In particular, the metabolic challenges faced by intracellular pathogens, such as Mycobacterium tuberculosis, residing in the infected host provide novel opportunities for therapeutic intervention (Fang et al, 2009).