In Search of Drug Targets for Mycobacterium tuberculosis.
Mycobacterium tuberculosis is the etiological agent for tuberculosis in humans. The studies related to survival of this pathogen in the human host and development of drugs against reveal that the organism uses a complex physiology to adapt to the host environment. Many studies were targeted to key enzymes that allow this pathogen to either survive or remain latent within the host. Most of the models, which address the survival of pathogen, have evaluated limited dissolved oxygen and prevailing stress conditions. Hence, the truncated citric acid cycle, with the glyoxylate shunt was suggested as an option for survival of the pathogen and pathogenesis. We propose that the precursors to support this pathway could also be generated via enzymatic conversion involving poly-beta-hydroxybutyrate (PHB). We have used available genome sequence data and analyzed for the possible enzymatic conversions that can generate glyoxylate, acetyl CoA, and other enolases that can also be useful for various fatty acid transformations. The enzymes for accumulation and further hydrolysis of PHB were examined in sequence data analysis. The target enzymes were searched for in the genome using identified conserved domains. Using M. tuberculosis H37Rv as a model bacterium a supportive pathway has been envisaged and integrated with glyoxylate cycle to provide a complete option to pathogen for sustainable consumption of available carbon source(s). The study proposes that the enzymes of PHB synthesis and hydrolysis are possible targets for drug design, and that this should be considered when evaluating isocitrate lyase and malate synthase as targets.
Purohit
Hemant J
HJ
Environmental Genomics Unit, National Environmental Engineering Research Institute, CSIR, Nehru Marg, Nagpur 440020, India.
Cheema
Simrita
S
Lal
Sadhana
S
Raut
Chandrakant P
CP
Kalia
Vipin C
VC
D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy*; D005227:Fatty Acids / Q000096:biosynthesis; D016680:Genome, Bacterial; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D011091:Polyesters / Q000378:metabolism; D000091402:Prohibitins; D053038:Quorum Sensing; D017422:Sequence Analysis, DNA; D000094122:Polyhydroxybutyrates
D000995:Antitubercular Agents; D005227:Fatty Acids; D006885:Hydroxybutyrates; D011091:Polyesters; D000091402:Prohibitins; C000717328:PHB protein, human; C003182:poly-beta-hydroxybutyrate; D000094122:Polyhydroxybutyrates