期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 128, 期 40, 页码 13235-13242出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja063715w
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资金
- NIAID NIH HHS [R01 AI062968, AI062968, R01 AI063517, R56 AI062968, R01AI063517-01, R56 AI062968-01A1] Funding Source: Medline
- NIGMS NIH HHS [GM54072, R56 GM054072, R01 GM054072] Funding Source: Medline
- PHS HHS [H75/CCH623342] Funding Source: Medline
beta-Lactamases are one of the major causes of antibiotic resistance in Gram negative bacteria. The continuing evolution of beta-lactamases that are capable of hydrolyzing our most potent beta-lactams presents a vexing clinical problem, in particular since a number of them are resistant to inhibitors. The efficient inhibition of these enzymes is therefore of great clinical importance. Building upon our previous structural studies that examined tazobactam trapped as a trans-enamine intermediate in a deacylation deficient SHV variant, we designed a novel penam sulfone derivative that forms a more stable trans-enamine intermediate. We report here the 1.28 angstrom resolution crystal structure of wt SHV-1 in complex with a rationally designed penam sulfone, SA2-13. The compound is covalently bound to the active site of wt SHV-1 similar to tazobactam yet forms an additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to stabilize the trans-enamine intermediate. Kinetic measurements show that SA2-13, once reacted with SHV-1 beta-lactamase, is about 10-fold slower at being released from the enzyme compared to tazobactam. Stabilizing the trans-enamine intermediate represents a novel strategy for the rational design of mechanism-based class A beta-lactamase inhibitors.
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