Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases

被引：326

作者：

Hecker, Scott J. ^{[1
]}

Reddy, K. Raja ^{[1
]}

Totrov, Maxim ^{[2
]}

Hirst, Gavin C. ^{[1
]}

Lomovskaya, Olga ^{[1
]}

Griffith, David C. ^{[1
]}

King, Paula ^{[1
]}

Tsivkovski, Ruslan ^{[1
]}

Sun, Dongxu ^{[1
]}

Sabet, Mojgan ^{[1
]}

Tarazi, Ziad ^{[1
]}

Clifton, Matthew C. ^{[3
]}

Atkins, Kateri ^{[3
]}

Raymond, Amy ^{[3
]}

Potts, Kristy T. ^{[3
]}

Abendroth, Jan ^{[3
]}

Boyer, Serge H. ^{[1
]}

Loutit, Jeffrey S. ^{[1
]}

Morgan, Elizabeth E. ^{[1
]}

Durso, Stephanie ^{[1
]}

Dudley, Michael N. ^{[1
]}

机构：

[1] A Subsidiary Med Co, Rempex Pharmaceut Inc, San Diego, CA 92121 USA

[2] Molsoft LLC, San Diego, CA 92121 USA

[3] Beryllium, Bedford, MA 01730 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 09期

基金：

美国国家卫生研究院;

关键词：

TRANSITION-STATE ANALOG; STRUCTURE-BASED DESIGN; ENTEROBACTERIACEAE; RESISTANCE; HYDROLYSIS; COMPLEXES; SUBSTRATE; ACYL;

D O I：

10.1021/acs.jmedchem.5b00127

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the beta-lactam class of antimicrobials. A program was initiated to discover a new series of serine beta-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine beta-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.

引用

页码：3682 / 3692

页数：11

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