Over-activation of a nonessential bacterial protease DegP as an antibiotic strategy.
Over-activation of a nonessential bacterial protease DegP as an antibiotic strategy.
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DOI：
10.1038/s42003-020-01266-9
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发表时间：
2020-10-01
影响因子：
5.9
通讯作者：
Kim S
中科院分区：
文献类型：
--
作者：
Cho H;Choi Y;Min K;Son JB;Park H;Lee HH;Kim S
Rising antibiotic resistance urgently begs for novel targets and strategies for antibiotic discovery. Here, we report that over-activation of the periplasmic DegP protease, a member of the highly conserved HtrA family, can be a viable strategy for antibiotic development. We demonstrate that tripodal peptidyl compounds that mimic DegP-activating lipoprotein variants allosterically activate DegP and inhibit the growth of an Escherichia coli strain with a permeable outer membrane in a DegP-dependent fashion. Interestingly, these compounds inhibit bacterial growth at a temperature at which DegP is not essential for cell viability, mainly by over-proteolysis of newly synthesized proteins. Co-crystal structures show that the peptidyl arms of the compounds bind to the substrate-binding sites of DegP. Overall, our results represent an intriguing example of killing bacteria by activating a non-essential enzyme, and thus expand the scope of antibiotic targets beyond the traditional essential proteins or pathways. Hyunjin Cho et al. show that peptidyl compounds activating the periplasmic DegP protease inhibit the growth of Escherichia coli by promoting the proteolysis of newly synthesized proteins. This study presents an intriguing strategy to combat antibiotic resistance by activating a non-essential bacterial enzyme, thus expanding the scope of traditional antibiotic targets.
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DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fischbach MA;Walsh CT
通讯作者：
Walsh CT
影响因子：
14.8
作者：
Heinis, Christian;Rutherford, Trevor;Winter, Greg
通讯作者：
Winter, Greg
影响因子：
16.8
作者：
Lee, Byung-Gil;Park, Eun Young;Song, Hyun Kyu
通讯作者：
Song, Hyun Kyu
DOI：
10.1073/pnas.1204791109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Kim, Seokhee;Sauer, Robert T.
通讯作者：
Sauer, Robert T.
影响因子：
120.1
作者：
Drag, Marcin;Salvesen, Guy S.
通讯作者：
Salvesen, Guy S.