Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

被引：207

作者：

Brem, Juergen ^{[1
]}

Cain, Ricky ^{[2
]}

Cahill, Samuel ^{[1
]}

McDonough, Michael A. ^{[1
]}

Clifton, Ian J. ^{[1
]}

Jimenez-Castellanos, Juan-Carlos ^{[3
]}

Avison, Matthew B. ^{[3
]}

Spencer, James ^{[3
]}

Fishwick, Colin W. G. ^{[2
]}

Schofield, Christopher J. ^{[1
]}

机构：

[1] Univ Oxford, Dept Chem, 12 Mansfield Rd, Oxford OX1 3TA, England

[2] Univ Leeds, Sch Chem, Leeds LS2 9JT, W Yorkshire, England

[3] Univ Bristol, Sch Cellular & Mol Med, Biomed Sci Bldg, Bristol BS8 1TD, Avon, England

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国工程与自然科学研究理事会; 英国医学研究理事会;

关键词：

CRYSTAL-STRUCTURES; RAMA; ACID; COMBINATIONS; HYDROLYSIS; COMPLEXES;

D O I：

10.1038/ncomms12406

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

beta-Lactamases enable resistance to almost all beta-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-beta-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent beta-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-beta-lactamases, and which could also have antimicrobial activity through inhibition of PBPs.

引用

页数：8

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