thiolactomycin and Tuberculosis

Development of new chemotherapeutic drugs is the need of the hour to improve tuberculosis control, particularly in the developing world. In the last fourty years no new compound has been brought to the market for the treatment of tuberculosis. However, in recent years there is an enhanced activity in the research and development of new drugs for TB. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Simultaneously some new targets are being identified and validated for their practical usefulness. Structures based on thiolactomycin could have considerable potential in the development of target based anti-TB agents. The present review provides an overview of the drugs that are being clinically used and the compounds that are in advanced stages of clinical as well as preclinical studies. We have also attempted to highlight the efforts that are being made in the development of new molecules based on thiolactomycin as lead compound, including studies from this laboratory.

Topics: Animals; Antitubercular Agents; Drug Design; Ethambutol; Isoniazid; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Physiological Phenomena; Pyrazinamide; Rifamycins; Streptomycin; Thiophenes; Tuberculosis; Tuberculosis, Pulmonary

The survival of Mycobacterium tuberculosis depends on mycolic acids, very long α-alkyl-β-hydroxy fatty acids comprising 60-90 carbon atoms. However, despite considerable efforts, little is known about how enzymes involved in mycolic acid biosynthesis recognize and bind their hydrophobic fatty acyl substrates. The condensing enzyme KasA is pivotal for the synthesis of very long (C38-42) fatty acids, the precursors of mycolic acids. To probe the mechanism of substrate and inhibitor recognition by KasA, we determined the structure of this protein in complex with a mycobacterial phospholipid and with several thiolactomycin derivatives that were designed as substrate analogs. Our structures provide consecutive snapshots along the reaction coordinate for the enzyme-catalyzed reaction and support an induced fit mechanism in which a wide cavity is established through the concerted opening of three gatekeeping residues and several α-helices. The stepwise characterization of the binding process provides mechanistic insights into the induced fit recognition in this system and serves as an excellent foundation for the development of high affinity KasA inhibitors.

Topics: Antitubercular Agents; Drug Delivery Systems; Enzyme Inhibitors; Fatty Acid Synthases; Mycobacterium tuberculosis; Mycolic Acids; Protein Structure, Secondary; Protein Structure, Tertiary; Tuberculosis

Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (mtFabH) has been identified as a novel target for treating tuberculosis. The aim of this study was to understand the binding affinities of thiolactomycin (TLM) analogs for mtFabH based on 3D quantitative structure-activity relationship (3D-QSAR) analysis and molecular docking studies. The 3D-QSAR models produced statistically significant results (comparative molecular field analysis (CoMFA) r2 cv = 0.701, r(2) = 0.988; comparative molecular similarity indices analysis (CoMSIA) r2 cv = 0.625, r(2) = 0.969) with 40 TLM analogs. In particular, compounds possessing hydrogen bond acceptors attached to the end of side chains at the C5 position of TLM analogs may enhance their activity. The results of 3D-QSAR models were further compared with structure-based analysis using docking studies with the crystal structure of mtFabH. A plausible binding mode between TLM analogs and mtFabH is proposed.

Topics: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Animals; Anti-Bacterial Agents; Binding Sites; Computer Simulation; Crystallography, X-Ray; Humans; Models, Molecular; Molecular Conformation; Mycobacterium tuberculosis; Protein Binding; Quantitative Structure-Activity Relationship; Thiophenes; Tuberculosis; User-Computer Interface