Opportunities and Challenges in Clinical and Preclinical Drug Development for Mycobacterium marinum

Over recent decades, non‐tuberculous mycobacterial infections have increased significantly. Mycobacterium marinum , a widely distributed environmental pathogen, can cause cutaneous and invasive diseases in humans and aquatic animals. Over the past century, our understanding of this pathogen has evolved from early descriptions of “swimming pool granuloma” to recognition of its intracellular lifestyle, granulomatous host responses, and genetic and functional similarities to Mycobacterium tuberculosis . Despite these advances, clinical management remains challenging. Current regimens are largely extrapolated from anti‐tuberculous therapy. These regimens show variable efficacy and require prolonged treatment durations, and there is a near‐total absence of randomized controlled trials specifically for M. marinum . The emergence of intrinsic and acquired resistance further complicates treatment decisions. On the preclinical front, drug screening using M. marinum as a surrogate model for tuberculosis has increased substantially over the past two decades, yet the translation of candidate compounds to clinical use remains slow. This Review examines the opportunities and persistent challenges in drug development for M. marinum over the past century, tracing the evolutionary trajectory from empirical combination therapy to mechanism‑based drug discovery. It outlines the pathogenic mechanisms of M. marinum , evaluates the resistance profiles of current clinical drugs and treatment regimens under clinical investigation, and introduces promising small‑molecule compounds. We also highlight critical knowledge gaps, including the near‐total absence of dedicated clinical trials for M. marinum , the lack of predictive animal models, poorly defined compound targets, and insufficient surveillance of drug resistance. Addressing these gaps is essential to translate preclinical progress into tangible clinical benefit and to close the long‑standing translational gap in this field.