Current Advances in Developing New Antimicrobial Agents Against Non-Tuberculous Mycobacterium

Non-tuberculous mycobacteria (NTM) comprise more than 190 species capable of causing severe pulmonary, lymphatic, cutaneous, and disseminated infections, particularly in immunocompromised populations. Over the past two decades, the global incidence of NTM infections has risen steadily, underscoring an urgent unmet medical need. Treatment remains highly challenging due to intrinsic antimicrobial resistance and the requirement for prolonged multidrug regimens that are often poorly tolerated and associated with unsatisfactory outcomes. At the same time, the development of novel therapies has lagged behind other disease areas, hindered by the high costs of antimicrobial drug discovery and the relatively low commercial return compared with treatments for chronic conditions. Over the past decade, discovery and development have diversified across novel small molecules, next-generation analogues of existing classes, and adjunctive or host-directed strategies. While most candidates remain preclinical, several agents have advanced clinically in other infections, including <b>gepotidacin</b> (topoisomerase inhibitor; FDA-approved 2025 for urinary tract infection (UTI)), sulbactam-<b>durlobactam</b> (DBO β-lactamase inhibitor; FDA-approved 2023 for <i>Acinetobacter baumannii</i> complex), and <b>contezolid</b>, supporting repurposing opportunities for NTM. Conversely, <b>SPR720</b> (gyrase B prodrug) was suspended after not meeting its Phase 2 endpoint in 2024, underscoring translational risk. Overall, the NTM pipeline is expanding, with near-term progress most likely from repurposed agents and optimised combinations, alongside earlier-stage candidates that target biofilms or resistance mechanisms. This review aims to provide a critical and up-to-date overview of emerging antimicrobial strategies against NTM, highlighting recent advances, translational challenges, and opportunities to accelerate the development of effective therapeutics.