Mycobacterium avium: Diversity, Clinical Significance, Old and New Targeted Medicines.

The Mycobacterium avium complex (MAC) comprises opportunistic pathogens of growing clinical significance, particularly in immunocompromised individuals and aging populations. Advances in molecular genomics have refined MAC taxonomy, enabling more precise diagnosis and informing therapeutic strategies. Whole-genome sequencing has revealed substantial genomic diversity within MAC, particularly in M. avium subsp. hominissuis (MAH), the predominant subspecies isolated from patients, and has helped identifying genetic determinants of strain-specific adaptation, virulence, and environmental persistence. The escalating incidence of MAH infections represents a pressing public health concern, further complicated by intrinsic and acquired antimicrobial resistance and the absence of standardized susceptibility testing. This review integrates recent developments in MAC taxonomy and epidemiology, with a particular focus on MAH pathogenesis, and provides an updated overview of the drug discovery landscape. We highlight innovative strategies, including novel antimicrobials and host-directed therapies, with the goal of developing safer, more effective medication. By linking mechanistic insights to translational applications, this work underscores the potential to improve clinical outcomes in patients affected by MAH infections and provides a framework for future precision-guided therapies.