Redefining Therapies for Drug-Resistant Tuberculosis: Synergistic Effects of Antimicrobial Peptides, Nanotechnology, and Computational Design.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health concern, particularly due to the emergence of multidrug-resistant and extensively drug-resistant strains. The persistence and propagation of TB are favored by the pathogen's sophisticated virulence mechanisms, its ability to evade immune responses, and the formation of latent infections within granulomas. Current therapeutic regimens are limited by long treatment durations, drug resistance, and significant socioeconomic burdens. Antimicrobial peptides (AMPs) have emerged as promising alternatives because of their broad-spectrum activity and reduced likelihood of resistance development. Nevertheless, their clinical application is hindered by rapid proteolytic degradation, low specificity and limited bioavailability. Recent advances in nanotechnology have facilitated the encapsulation and targeted delivery of AMPs, improving their therapeutic potential against TB. Furthermore, the integration of computational approaches-such as molecular docking and molecular dynamics (MD) simulations-has enabled the rational design and optimization of AMPs, expediting the discovery of novel anti-TB agents. This review summarizes the pathogenesis and resistance mechanisms of Mtb, highlights the current landscape and limitations of AMP-based therapies, and discusses the role of nanotechnology and in silico tools in the development of new treatment strategies for TB.