Structure-Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds.

The rise of antibiotic-resistant Mycobacterium tuberculosis and non-tuberculous mycobacterial infections has placed ever-increasing importance on discovering new antibiotics to treat these diseases. Recently, a new penem, T405 , was discovered to have strong antimicrobial activity against M. tuberculosis and Mycobacteroides abscessus . Here, a penem library of C2 side-chain variants was synthesized, and their antimicrobial activities were evaluated against M. tuberculosis H 37 Rv and M. abscessus ATCC 19977. Several new penems with antimicrobial activity stronger than the standard-of-care carbapenem antibiotics were identified with some candidates improving on the activity of the lead compound, T405 . Moreover, many candidates showed little or no increase in the minimum inhibitory concentration in the presence of serum compared to the highly protein-bound T405 . The penems with the strongest activity identified in this study were then biochemically characterized by reaction with the representative l,d-transpeptidase Ldt Mt2 and the representative penicillin-binding protein d,d-carboxypeptidase DacB2.