Mycobacterium marinum as a surrogate model for tuberculosis pathogenesis and drug discovery

Tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, driven by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains and the limited efficacy of current therapeutic strategies. Over the past two decades, Mycobacterium marinum (M. marinum), a close genetic relative of Mtb, has emerged as a powerful surrogate model for investigating conserved mechanisms of TB pathogenesis and accelerating early-stage therapeutic discovery. As a naturally pathogenic mycobacterium, M. marinum shares key virulence determinants with Mtb, including ESX-1-dependent secretion, intracellular survival strategies, lipid-mediated immune modulation, and the ability to induce granulomatous disease. Its compatibility with diverse experimental systems-ranging from macrophage cultures to genetically tractable vertebrate hosts such as zebrafish-enables real-time visualization of host-pathogen interactions, granuloma dynamics, immune regulation, and bacterial dissemination in vivo. In addition to mechanistic pathogenesis studies, M. marinum provides a scalable platform for phenotypic drug screening, host-directed therapeutic discovery, and early in vivo evaluation of antimicrobial candidates, thereby bridging the gap between in vitro assays and mammalian infection models. This review synthesizes recent advances in the use of M. marinum across pathogenesis research, functional genomics, and drug discovery, critically examining its strengths, limitations, and optimal positioning within multi-tiered tuberculosis research pipelines.