Mode of Action of the Monobactam LYS228 and Mechanisms Decreasing In Vitro Susceptibility in Escherichia coli and Klebsiella pneumoniae
| Autor: | Richard Colvin, Dita M. Rasper, Johanne Blais, Adriana K. Jones, Ramadevi Prathapam, Alexey Ruzin, Xiaoyu Shen, John Fuller, Anthony Casarez, Jun-Rong Wei, Sara Lopez, Alun Bermingham, Peter Skewes-Cox, Tsuyoshi Uehara, Pramila Tamrakar, David T. Barkan, Fergal Casey, Louis E. Metzger, Mina Mostafavi, Robert Lowell Simmons, Kenneth T. Takeoka, Charles R. Dean, Folkert Reck, Cindy Li, Jacob Shaul |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Penicillin binding proteins Klebsiella pneumoniae 030106 microbiology Tigecycline Aztreonam Microbial Sensitivity Tests medicine.disease_cause Meropenem beta-Lactamases Microbiology 03 medical and health sciences chemistry.chemical_compound Enterobacteriaceae Mechanisms of Resistance medicine Escherichia coli Monobactam Pharmacology (medical) Pharmacology biology Chemistry biology.organism_classification Anti-Bacterial Agents Infectious Diseases Mutation medicine.drug Monobactams |
| Popis: | The monobactam scaffold is attractive for the development of new agents to treat infections caused by drug-resistant Gram-negative bacteria because it is stable to metallo-β-lactamases (MBLs). However, the clinically used monobactam aztreonam lacks stability to serine β-lactamases (SBLs) that are often coexpressed with MBLs. LYS228 is stable to MBLs and most SBLs. LYS228 bound purified Escherichia coli penicillin binding protein 3 (PBP3) similarly to aztreonam (derived acylation rate/equilibrium dissociation constant [k(2)/K(d)] of 367,504 s(−1) M(−1) and 409,229 s(−1) M(−1), respectively) according to stopped-flow fluorimetry. A gel-based assay showed that LYS228 bound mainly to E. coli PBP3, with weaker binding to PBP1a and PBP1b. Exposing E. coli cells to LYS228 caused filamentation consistent with impaired cell division. No single-step mutants were selected from 12 Enterobacteriaceae strains expressing different classes of β-lactamases at 8× the MIC of LYS228 (frequency |
| Databáze: | OpenAIRE |
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