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Relacin,a Novel Antibacterial Agent Targeting the Stringent Response
Authors:Ezequiel Wexselblatt  Yaara Oppenheimer-Shaanan  Ilana Kaspy  Nir London  Ora Schueler-Furman  Eylon Yavin  Gad Glaser  Joshua Katzhendler  Sigal Ben-Yehuda
Institution:1. Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.; 2. Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, Israel.; 3. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, Israel.; Osaka University, Japan,
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.
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