Mycobacterial Membrane Targeting Synthetic Antimicrobial Peptides For Treatment Against Tuberculosis: A Systematic Review

ABSTRACT Tuberculosis (TB) remains a global health concern, primarily due to the alarming increase in multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains of Mycobacterium tuberculosis ( Mtb ) in recent years. To effectively overcome Mtb drug resistance mechanisms, innovative therapeutic modalities such as combinatorial therapy, which integrates conventional anti‐tubercular drugs with antimicrobial peptides (AMPs), are being actively investigated. In this review, we have attempted to establish the therapeutic rationale for proposing membrane‐targeting synthetic AMPs by focusing on the unique lipid composition and structural rigidity of the Mtb cell envelope. Subsequently, we evaluated the properties and molecular mechanisms of action of five key synthetic AMPs demonstrating potent antimicrobial activity against MDR and XDR strains of Mtb , which includes LLAP (a 15‐amino‐acid LL‐37 analogue); CP26 (a 26‐amino‐acid cecropin A / mellitin hybrid); D‐LAK120 (a 27‐amino‐acid containing synthetic AMP); hLF1‐11/ hLF1‐1117‐30 (an 11‐amino‐acid human lactoferrin derivative); and MIAP (a 19‐amino‐acid magainin derivative). A detailed comparative analysis on synthetic peptides' physicochemical properties, efficacy, safety profile, pharmacodynamic characteristics and mechanisms of action are addressed. Finally, we have reported the significant translational challenges associated with the clinical application of synthetic AMPs, including systemic delivery and stability. Based on these systematic analysis, we put forth that synthetic AMPs, when utilized in combination with existing drugs, represent a highly promising therapeutic modality for overcoming drug‐resistant tuberculosis infection.