Non-tuberculous mycobacteria (NTM), particularly Mycobacterium avium complex (MAC), have emerged as significant pulmonary pathogens. Current first-line treatments for pulmonary MAC disease typically involve the macrolide azithromycin (AZM). However, the increasing prevalence of drug-resistant MAC has created an urgent need for new therapeutics. Here, we present a novel series of Glc-AZM derivatives, KU15 to KU27, featuring C11 glucosyl moieties designed to anchor the macrolide to the ribosome and enhance antibacterial activity. These compounds were selectively synthesized using our boron-mediated aglycon delivery (BMAD) method. A structure-activity relationship (SAR) study on the macrolides' C11 substituents identified KU22 and KU20, both containing a terminal pyridine structure, as exceptionally potent compounds, demonstrating a four-to sixteen-fold increase in efficacy over AZM and telithromycin (TEL) against wild-type M. avium and M. intracellulare, respectively. Furthermore, the SAR analysis showed that KU13, a previously developed AZM derivative, was the most potent compound against macrolide-resistant MAC, while also retaining activity against wild-type strains. Taking advantage of its mild reaction conditions, the BMAD method was successfully implemented for gram-scale, one-pot modification of AZM to synthesize KU13. KU13 exhibited no inhibition of mammalian translation and, most importantly, demonstrated pronounced in vivo efficacy in a mouse model of MAC infection. Our findings establish KU13 as a promising new lead compound for the treatment of drug-resistant MAC infection.
