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. tubercul...
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Published in | ACS infectious diseases Vol. 8; no. 8; pp. 1627 - 1636 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
12.08.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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 H37Rv 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 LdtMt2 and the representative penicillin-binding protein d,d-carboxypeptidase DacB2. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The study was conceived and directed by C.A.T, G.L., and E.L.N. Synthesis of all new penems was carried out by H.R.B. and A.N. A.K., E.S-R., and E.C.M. undertook microbiological studies, and with E.L.N. and G.L. analyzed the data. T.A.Z. expressed and purified LdtMt2 and DacB2. T.A.Z. performed intact protein UPLC–MS experiments and interpreted the data. H.R.B,,T.A.Z., C.A.T., G.L, and E.L.N. all contributed to the interpretation of data and writing the paper. Author Contributions |
ISSN: | 2373-8227 2373-8227 |
DOI: | 10.1021/acsinfecdis.2c00229 |