Small molecules play important roles in both the establishment and propagation of bacterial infections. Although the characterization of small molecules produced by bacterial pathogens grown under controlled conditions in the laboratory has led to the discovery of many important signaling molecules and toxins, laboratory fermentation conditions are not representative of the growth conditions under which an infection occurs. Laboratory based fermentation studies are therefore unlikely to have provided access to the full repertoire of molecules used by bacterial pathogens during an infection. Cryptic small molecule biosynthetic gene clusters, gene clusters that do not appear to encode the biosynthesis of any known metabolites, are routinely found in sequenced bacterial genomes. These cryptic pathways represent the pool of pathways from which additional signaling systems and toxins will be found in bacterial pathogens. The work outlined in this proposal will provide access to previously unknown molecules encoded by the cryptic biosynthetic pathways found in the genomes of biodefense relevant bacterial pathogens. A detailed analysis of the genomes of many biodefense relevant pathogens suggests that they contain numerous previously unknown gene clusters that likely code for the biosynthesis of, as yet, unidentified small molecules. The genomics based approaches that we are using for the discovery of small molecules should result in a more complete description of the complex networks of small molecule signals and toxins that are used by biodefense relevant bacterial pathogens;and as a result, provide novel insights into how best to disrupt key steps in the establishment and propagation of bacterial infections.
The work proposed here will provide access to novel small molecules encoded by the genomes of biodefense relevant bacterial pathogens. The characterization of new small molecule based signaling systems and new toxin biosynthetic pathways should provide novel insights into how best to manipulate biodefense relevant bacterial pathogens for the benefit of human health.
|Li, Xiao-Ping; Kahn, Jennifer N; Tumer, Nilgun E (2018) Peptide Mimics of the Ribosomal P Stalk Inhibit the Activity of Ricin A Chain by Preventing Ribosome Binding. Toxins (Basel) 10:|
|Goldman, David L; Nieves, Edward; Nakouzi, Antonio et al. (2018) Serum-Mediated Cleavage of Bacillus anthracis Protective Antigen Is a Two-Step Process That Involves a Serum Carboxypeptidase. mSphere 3:|
|Marié, Isabelle J; Chang, Hao-Ming; Levy, David E (2018) HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies. J Exp Med 215:3194-3212|
|Uhde, Melanie; Ajamian, Mary; Wormser, Gary P et al. (2017) Reply to Naktin. Clin Infect Dis 64:1145-1146|
|Chen, Han; Coseno, Molly; Ficarro, Scott B et al. (2017) A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions. ACS Infect Dis 3:112-118|
|Aguilar, Jorge L; Varshney, Avanish K; Pechuan, Ximo et al. (2017) Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus. Virulence 8:741-750|
|Zhou, Yijun; Li, Xiao-Ping; Chen, Brian Y et al. (2017) Ricin uses arginine 235 as an anchor residue to bind to P-proteins of the ribosomal stalk. Sci Rep 7:42912|
|Moser, Lindsey A; Lim, Pei-Yin; Styer, Linda M et al. (2016) Parameters of Mosquito-Enhanced West Nile Virus Infection. J Virol 90:292-9|
|Li, Melody M H; Bozzacco, Leonia; Hoffmann, Hans-Heinrich et al. (2016) Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion. J Exp Med 213:2931-2947|
|Charles, Jermilia; Firth, Andrew E; Loroño-Pino, Maria A et al. (2016) Merida virus, a putative novel rhabdovirus discovered in Culex and Ochlerotatus spp. mosquitoes in the Yucatan Peninsula of Mexico. J Gen Virol 97:977-87|
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