Identification of Missing Carbon Fixation Enzymes as Potential Drug Targets in Mycobacterium Tuberculosis.

Abstract

Metabolic adaptation to the host environment has been recognized as an essential mechanism of pathogenicity and the growth of Mycobacterium tuberculosis (Mtb) in the lungs for decades. The Mtb uses CO2 as a source of carbon during the dormant or non-replicative state. However, there is a lack of biochemical knowledge of its metabolic networks. In this study, we investigated the CO2 fixation pathways (such as ko00710 and ko00720) most likely involved in the energy production and conversion of CO2 in Mtb. Extensive pathway evaluation of 23 completely sequenced strains of Mtb confirmed the existence of a complete list of genes encoding the relevant enzymes of the reductive tricarboxylic acid (rTCA) cycle. This provides the evidence that an rTCA cycle may function to fix CO2 in this bacterium. We also proposed that as CO2 is plentiful in the lungs, inhibition of CO2 fixation pathways (by targeting the relevant CO2 fixation enzymes) could be used in the expansion of new drugs against the dormant Mtb. In support of the suggested hypothesis, the CO2 fixation enzymes were confirmed as a potential drug target by analyzing a number of attributes necessary to be a good bacterial target.