期刊
BIOCHEMISTRY
卷 54, 期 10, 页码 1976-1987出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi501547k
关键词
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资金
- National Institutes of Health [1R15AI082416, R15AI094489]
- Cleveland Department of Veterans Affairs
- Department of Veterans Affairs Merit Review Program [1I01BX001974]
- Veterans Integrated Service Network 10 Geriatric Research, Education, and Clinical Center (VISN 10 GRECC)
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01 AI100560, R01 AI063517]
- National Center for Multiscale Modeling of Biological Systems (MMBioS) through National Institutes of Health [P41GM103712]
- U.S. DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI063517, R01AI100560, R01AI072219, R15AI094489, R15AI082416] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103712] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX001974] Funding Source: NIH RePORTER
The carbapenem-hydrolyzing class D beta-lactamases OXA-23 and OXA-24/40 have emerged worldwide as causative agents for beta-lactam antibiotic resistance in Acinetobacter species. Many Variants of these enzymes have appeared clinically, including OXA-160 and OXA-225, which both contain a P -> S substitution at homologous positions in the OXA-24/40 and OXA-23 background's, respectively. We purified OXA-160 and OXA-225 and used steady-State kinetic analysis to compare the substrate profiles of these variants to their parental enzymes, OXA-24/40 and OXA-23. OXA-160 and OXA-225 possess greatly enhanced hydrolytic activities against aztreonam, ceftazidime, cefotaxime, and ceftriaxone when compared to OXA-24/40 and OXA-23. These enhanced activities are the result of much lower K-m values, suggesting that the P -> S substitution enhances the binding affinity of these drugs. We have determined the structures of the acylated forms of OXA-160 (with ceftazidime and aztreonam) and OXA-225 (ceftazidime). These structures show that the R1 oxyimino side-chain of these drugs occupies a space near the beta 5-beta 6 loop and the omega loop of the enzymes. The P -> S substitution found in OXA-160 and OXA-225 results in a deviation of the beta 5-beta 6 loop, relieving the steric dash with the R1 side-chain carboxypropyl group of aztreonam and ceftazidime. These results reveal worrying trends in the enhancement of substrate spectrum of class beta-lactamases but may also provide a map for Chi-lactam improvement.
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