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.
|Charles, Jermilia; Firth, Andrew E; LoroÃ±o-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|
|Pham, Alissa M; Santa Maria, Felicia Gilfoy; Lahiri, Tanaya et al. (2016) PKR Transduces MDA5-Dependent Signals for Type I IFN Induction. PLoS Pathog 12:e1005489|
|Song, Jeongmin; Wilhelm, Cara L; Wangdi, Tamding et al. (2016) Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi. Cell 164:827-8|
|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|
|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|
|Basu, Debaleena; Kahn, Jennifer N; Li, Xiao-Ping et al. (2016) Conserved Arginines at the P-Protein Stalk Binding Site and the Active Site Are Critical for Ribosome Interactions of Shiga Toxins but Do Not Contribute to Differences in the Affinity of the A1 Subunits for the Ribosome. Infect Immun 84:3290-3301|
|Steyer, Andrej; JevÅ¡nik, Monika; Petrovec, Miroslav et al. (2016) Narrowing of the Diagnostic Gap of Acute Gastroenteritis in Children 0-6 Years of Age Using a Combination of Classical and Molecular Techniques, Delivers Challenges in Syndromic Approach Diagnostics. Pediatr Infect Dis J 35:e262-70|
|Uhde, Melanie; Ajamian, Mary; Li, Xueting et al. (2016) Expression of C-Reactive Protein and Serum Amyloid A in Early to Late Manifestations of Lyme Disease. Clin Infect Dis 63:1399-1404|
|Jacek, Elzbieta; Tang, Kevin S; Komorowski, Lars et al. (2016) Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease. J Immunol 196:1036-43|
|Aguilar, Jorge L; Varshney, Avanish K; Pechuan, Ximo et al. (2016) Monoclonal antibodies protect from Staphylococcal Enterotoxin K (SEK) induced toxic shock and sepsis by USA300 Staphylococcus aureus. Virulence :1-10|
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