The Mycobactin Biosynthesis Pathway: A Prospective Therapeutic Target in the Battle against Tuberculosis

• Published in: Journal of medicinal chemistry Vol. 64; no. 1; pp. 71 - 100
• Main Authors: Shyam, Mousumi, Shilkar, Deepak, Verma, Harshita, Dev, Abhimanyu, Sinha, Barij Nayan, Brucoli, Federico, Bhakta, Sanjib, Jayaprakash, Venkatesan
• Format: Journal Article
• Language: English
• Published: United States 14.01.2021
• Subjects: Antitubercular Agents - pharmacology; Bacterial Proteins - metabolism; Biosynthetic Pathways; Drug Discovery; Drug Resistance, Bacterial - drug effects; Humans; Iron - metabolism; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; Oxazoles - metabolism; Tuberculosis - drug therapy
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01176

The alarming rise in drug-resistant clinical cases of tuberculosis (TB) has necessitated the rapid development of newer chemotherapeutic agents with novel mechanisms of action. The mycobactin biosynthesis pathway, conserved only among the mycolata family of actinobacteria, a group of intracellularly surviving bacterial pathogens that includes , generates a salicyl-capped peptide mycobactin under iron-stress conditions in host macrophages to support the iron demands of the pathogen. This essentiality makes this less explored mycobactin biosynthesis pathway a promising endogenous target for novel lead-compounds discovery. In this Perspective, we have provided an up-to-date account of drug discovery efforts targeting selected enzymes (MbtI, MbtA, MbtM, and PPTase) from the gene cluster ( ). Furthermore, a succinct discussion on non-specific mycobactin biosynthesis inhibitors and the Trojan horse approach adopted to impair iron metabolism in mycobacteria has also been included in this Perspective.