期刊
ACS INFECTIOUS DISEASES
卷 4, 期 3, 页码 349-359出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.7b00122
关键词
SOS response; LexA; RecA; antimicrobial resistance; antivirulence; high-throughput screening
资金
- National Institutes of Health [DP2-GM105444, T32-GM7229, T32-GM071399, T32-AI060516, T32-AR007442]
- Harrington Discovery Institute Scholar Innovator Award
- Edward J. Mallinckrodt, Jr., Foundation
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI060516, T32AI118684] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [T32AR007442] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [K23GM071399, T32GM007229, DP2GM105444] Funding Source: NIH RePORTER
The RecA/LexA axis of the bacterial DNA damage (SOS) response is a promising, yet nontraditional, drug target. The SOS response is initiated upon genotoxic stress, when RecA, a DNA damage sensor, induces LexA, the SOS repressor, to undergo autoproteolysis, thereby derepressing downstream genes that can mediate DNA repair and accelerate mutagenesis. As genetic inhibition of the SOS response sensitizes bacteria to DNA damaging antibiotics and decreases acquired resistance, inhibitors of the RecA/LexA axis could potentiate our current antibiotic arsenal. Compounds targeting RecA, which has many mammalian homologues, have been reported; however, small-molecules targeting LexA autoproteolysis, a reaction unique to the prokaryotic SOS response, have remained elusive. Here, we describe the logistics and accomplishments of an academic - industry partnership formed to pursue inhibitors against the RecA/LexA axis. A novel fluorescence polarization assay reporting on RecA-induced self-cleavage of LexA enabled the screening of 1.8 million compounds. Follow-up studies on select leads show distinct activity patterns in orthogonal assays, including several with activity in cell-based assays reporting on SOS activation. Mechanistic assays demonstrate that we have identified first-in-class small molecules that specifically target the LexA autoproteolysis step in SOS activation. Our efforts establish a realistic example for navigating academic - industry partnerships in pursuit of anti-infective drugs and offer starting points for dedicated lead optimization of SOS inhibitors that could act as adjuvants for current antibiotics.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据