Peptide-Based Strategies Against Mycobacterium tuberculosis Covering Immunomodulation, Vaccines, Synergistic Therapy,...

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the most devastating infectious diseases worldwide, with rising multidrug resistance limiting the effectiveness of conventional treatments. Novel therapeutic approaches are urgently needed to complement or replace existing regimens. Among emerging candidates, antimicrobial peptides (AMPs) stand out as versatile molecules capable of exerting direct antimycobacterial effects while also modulating the host immune response. This review explores peptide-based strategies against TB, with a focus on four major axes of innovation. First, we examine host-directed pathways, including the vitamin D-cathelicidin axis and other immunomodulatory mechanisms and their regulatory role in the induction of endogenous AMPs such as cathelicidin LL-37, which contributes to host-directed defense. Second, we discuss peptide-based vaccines designed to elicit robust and durable protective immunity, representing a complementary alternative to classical vaccine approaches. Third, we highlight the synergistic potential of AMPs in combination with first-line and second-line anti-TB drugs, aiming to restore or enhance bactericidal activity against resistant strains. Finally, we analyze technological platforms, including nanocarriers and inhalable formulations, that enable targeted pulmonary delivery, improve peptide stability, and enhance bioavailability. By integrating molecular design, immune modulation, and advanced delivery systems, peptide-based strategies provide a multifaceted approach to overcoming the limitations of current TB therapy. Collectively, these advances position AMPs not only as promising standalone agents but also as key components in combination and host-directed therapies, with strong potential to reshape the future clinical management of tuberculosis.