title: Relacin, a novel antibacterial agent targeting the Stringent Response.
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.
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Wexselblatt
authors.forename: Yaara
authors.initials: Y
authors.lastname: Oppenheimer-Shaanan
authors.forename: Ilana
authors.initials: I
authors.lastname: Kaspy
authors.forename: Nir
authors.initials: N
authors.lastname: London
authors.forename: Ora
authors.initials: O
authors.lastname: Schueler-Furman
authors.forename: Eylon
authors.initials: E
authors.lastname: Yavin
authors.forename: Gad
authors.initials: G
authors.lastname: Glaser
authors.forename: Joshua
authors.initials: J
authors.lastname: Katzhendler
authors.forename: Sigal
authors.initials: S
authors.lastname: Ben-Yehuda
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D001412:Bacillus subtilis / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018441:Biofilms / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006159:Guanosine Tetraphosphate / Q000378:metabolism*; D008025:Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D013171:Spores, Bacterial / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; C580565:relacin; D006159:Guanosine Tetraphosphate; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases; D003849:Deoxyguanosine