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 inACS infectious diseases Vol. 8; no. 8; pp. 1627 - 1636
Main Authors Batchelder, Hunter R., Zandi, Trevor A., Kaushik, Amit, Naik, Akul, Story-Roller, Elizabeth, Maggioncalda, Emily C., Lamichhane, Gyanu, Nuermberger, Eric L., Townsend, Craig A.
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 12.08.2022
Subjects
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Humans
Meropenem
Mycobacterium tuberculosis
Structure-Activity Relationship
Tuberculosis, Multidrug-Resistant
antibiotic
penem
structure−activity relationship
M. abscessus
β-lactam
M. tuberculosis
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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 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.
AbstractList 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.
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.
The rise of antibiotic-resistant and non-tuberculous mycobacterial infections has placed ever-increasing importance on discovering new antibiotics to treat these diseases. Recently, a new penem, , was discovered to have strong antimicrobial activity against and . Here, a penem library of C2 side-chain variants was synthesized, and their antimicrobial activities were evaluated against H Rv and 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, . Moreover, many candidates showed little or no increase in the minimum inhibitory concentration in the presence of serum compared to the highly protein-bound . The penems with the strongest activity identified in this study were then biochemically characterized by reaction with the representative l,d-transpeptidase Ldt and the representative penicillin-binding protein d,d-carboxypeptidase DacB2.
Author Batchelder, Hunter R.
Kaushik, Amit
Townsend, Craig A.
Naik, Akul
Zandi, Trevor A.
Nuermberger, Eric L.
Lamichhane, Gyanu
Maggioncalda, Emily C.
Story-Roller, Elizabeth
AuthorAffiliation Department of Chemistry
T. C. Jenkins Department of Biophysics
Johns Hopkins University
Johns Hopkins University School of Medicine
Center for Tuberculosis Research, Division of Infectious Diseases
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Keywords antibiotic
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structure−activity relationship
M. abscessus
β-lactam
M. tuberculosis
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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.
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Snippet The rise of antibiotic-resistant Mycobacterium tuberculosis and non-tuberculous mycobacterial infections has placed ever-increasing importance on discovering...
The rise of antibiotic-resistant and non-tuberculous mycobacterial infections has placed ever-increasing importance on discovering new antibiotics to treat...
The rise of antibiotic-resistant Mycobacterium tuberculosis and non- tuberculous mycobacterial infections has placed ever-increasing importance on discovering...
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SubjectTerms Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Humans
Meropenem
Mycobacterium tuberculosis
Structure-Activity Relationship
Tuberculosis, Multidrug-Resistant
Title Structure–Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds
URI http://dx.doi.org/10.1021/acsinfecdis.2c00229
https://www.ncbi.nlm.nih.gov/pubmed/35916356
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