Abstract
Finding bacterial cellular targets for developing novel antibiotics has become a major challenge in fighting resistant pathogenic bacteria. We present a novel compound, Relacin, designed to inhibit (p)ppGpp production by the ubiquitous bacterial enzyme RelA that triggers the Stringent Response. Relacin inhibits RelA in vitro and reduces (p)ppGpp production in vivo. Moreover, Relacin affects entry into stationary phase in Gram positive bacteria, leading to a dramatic reduction in cell viability. When Relacin is added to sporulating Bacillus subtilis cells, it strongly perturbs spore formation regardless of the time of addition. Spore formation is also impeded in the pathogenic bacterium Bacillus anthracis that causes the acute anthrax disease. Finally, the formation of multicellular biofilms is markedly disrupted by Relacin. Thus, we establish that Relacin, a novel ppGpp analogue, interferes with bacterial long term survival strategies, placing it as an attractive new antibacterial agent.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / pharmacology*
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Bacillus anthracis / drug effects*
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Bacillus anthracis / metabolism
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Bacillus anthracis / physiology
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Bacillus subtilis / drug effects*
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Bacillus subtilis / metabolism
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Bacillus subtilis / physiology
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Biofilms / drug effects
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Deoxyguanosine / analogs & derivatives*
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Deoxyguanosine / chemistry
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Deoxyguanosine / pharmacology
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Dipeptides / chemistry
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Dipeptides / pharmacology*
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Gene Expression Regulation, Bacterial / drug effects
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Guanosine Tetraphosphate / metabolism*
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Ligases / antagonists & inhibitors*
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Ligases / metabolism
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Microbial Sensitivity Tests
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Spores, Bacterial / drug effects
Substances
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Anti-Bacterial Agents
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Dipeptides
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relacin
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Guanosine Tetraphosphate
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Ligases
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guanosine 3',5'-polyphosphate synthetases
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Deoxyguanosine
Grants and funding
This work was supported by the European Research Council (ERC, erc.europa.eu) Starting Grant (209130) awarded to SBY, the Israeli National Academy of Science Foundation (ISF,
www.isf.org.il) Grant (374/08) awarded to GG and the German-Israeli Foundation (GIF,
www.gif.org.il) Grant (835/2004 and 943-334.9/2006) awarded to JK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.