Bacterial culture broth extracts have been the starting point for the development of numerous therapeutics. However, only a small fraction of bacterial biosynthetic diversity is accessible using this strategy. Here, we apply a discovery approach that bypasses the culturing step entirely by bioinformatically predicting small molecule structures from the primary sequences of the biosynthetic gene clusters. These structures are then chemically synthesized to give synthetic-bioinformatic natural products (syn-BNPs). Using this approach, we screened syn-BNPs inspired by nonribosomal peptide synthetases against microbial pathogens, and discovered an antibiotic for which no resistance could be identified and an antifungal agent with activity against diverse fungal pathogens.
Bacterial culture broth extracts have been the starting point for the development of numerous therapeutics. However, only a small fraction of bacterial biosynthetic diversity is accessible using this strategy. Here, we apply a discovery approach that bypasses the culturing step entirely by bioinformatipan class="Species">cally predicting small molecule structures from the primary sequences of the biosynthetic gene clusters. These structures are then chemically synthesized to give synthetic-bioinformatic natural products (syn-BNPs). Using this approach, we screened syn-BNPs inspired by nonribosomal peptide synthetases against microbial pathogens, and discovered an antibiotic for which no resistance could be identified and an antifungal agent with activity against diverse fungal pathogens.
Authors: Christopher T Lohans; Marco J van Belkum; Stephen A Cochrane; Zedu Huang; Clarissa S Sit; Lynn M McMullen; John C Vederas Journal: Chembiochem Date: 2013-12-30 Impact factor: 3.164
Authors: Hilmar Wisplinghoff; Jenny Ebbers; Lea Geurtz; Danuta Stefanik; Yvette Major; Michael B Edmond; Richard P Wenzel; Harald Seifert Journal: Int J Antimicrob Agents Date: 2013-10-12 Impact factor: 5.283
Authors: Marc Röttig; Marnix H Medema; Kai Blin; Tilmann Weber; Christian Rausch; Oliver Kohlbacher Journal: Nucleic Acids Res Date: 2011-05-09 Impact factor: 16.971
Authors: James R Doroghazi; Jessica C Albright; Anthony W Goering; Kou-San Ju; Robert R Haines; Konstantin A Tchalukov; David P Labeda; Neil L Kelleher; William W Metcalf Journal: Nat Chem Biol Date: 2014-09-28 Impact factor: 15.040
Authors: John Chu; Xavier Vila-Farres; Daigo Inoyama; Ricardo Gallardo-Macias; Mark Jaskowski; Shruthi Satish; Joel S Freundlich; Sean F Brady Journal: ACS Infect Dis Date: 2017-09-11 Impact factor: 5.084
Authors: John Chu; Bimal Koirala; Nicholas Forelli; Xavier Vila-Farres; Melinda A Ternei; Thahmina Ali; Dominic A Colosimo; Sean F Brady Journal: J Am Chem Soc Date: 2020-08-11 Impact factor: 15.419