Antimycobacterial peptides as natural therapeutics for tuberculosis: mechanisms and structural features

The disease tuberculosis, caused by Mycobacterium tuberculosis, is one of the leading causes of global human mortality. The rise of multidrug and extensively drug-resistant strains of the pathogen and the limited efficacy of the BCG vaccine is one of the major concerns worldwide. Conventional chemotherapy for tuberculosis is often very long and has several side effects. These factors lead to an urgent need for alternative, non-toxic therapeutic strategies with minimal side effects. Antimycobacterial peptides (AMPs), are a class of natural compounds that have shown a broad spectrum of anti-mycobacterial activity with a low propensity for the development of anti-mycobacterial resistance. This review summarizes the current antimycobacterial peptides, highlighting their structural features, physicochemical determinants, and their mechanism of action. Some of the key peptides have been critically discussed with respect to their membrane targeting mechanism. The role of structural modifications, such as disulfide bonding, cyclization, hydrophobicity tuning, and post-translational modifications, in enhancing antimycobacterial efficacy and stability is also examined. Consequently, the broad mechanism of action of these peptides and their role in the development of anti-tuberculosis drugs have been emphasized. This article combines mechanistic and structural insights to show how antimycobacterial peptides could become new anti-TB drugs. It also provides a guide for developing and improving peptide therapies for tuberculosis.