Non-tuberculous mycobacterial (NTM) lung disease, now more prevalent than tuberculosis in the U.S., has severely limited treatment options, resulting in significant morbidity and mortality. Among NTMs, Mycobacterium avium complex (MAC) is the most common pathogen. This proposal aims to establish a new standard-of-care by developing innovative regimens to treat MAC lung disease, including synergistic combinations of existing and new antibiotics, dual β-lactam pairs, and simplified phase-specific sequenced monotherapy approaches using a validated mouse model of this disease.