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

Year: 2022

Type: article

Abstract: 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.

Source: ACS Infectious Diseases

DOI: 10.1021/acsinfecdis.2c00229