title: Targeting Bacterial Dsb Proteins for the Development of Anti-Virulence Agents.
abstract: Recent years have witnessed a dramatic increase in bacterial antimicrobial resistance and a decline in the development of novel antibiotics. New therapeutic strategies are urgently needed to combat the growing threat posed by multidrug resistant bacterial infections. The Dsb disulfide bond forming pathways are potential targets for the development of antimicrobial agents because they play a central role in bacterial pathogenesis. In particular, the DsbA/DsbB system catalyses disulfide bond formation in a wide array of virulence factors, which are essential for many pathogens to establish infections and cause disease. These redox enzymes are well placed as antimicrobial targets because they are taxonomically widespread, share low sequence identity with human proteins, and many years of basic research have provided a deep molecular understanding of these systems in bacteria. In this review, we discuss disulfide bond catalytic pathways in bacteria and their significance in pathogenesis. We also review the use of different approaches to develop inhibitors against Dsb proteins as potential anti-virulence agents, including fragment-based drug discovery, high-throughput screening and other structure-based drug discovery methods.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Vic 3083, Australia. rp2smith@students.latrobe.edu.au.
authors.forename: Roxanne P
authors.initials: RP
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Vic 3083, Australia. J.Paxman@latrobe.edu.au.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paxman
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Royal Parade, Parkville, Vic 3052, Australia. martin.scanlon@monash.edu.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Vic 3083, Australia. b.heras@latrobe.edu.au.
authors.forename: Begoña
authors.initials: B
authors.lastname: Heras
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D055808:Drug Discovery; D048168:Escherichia coli K12 / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D018384:Oxidative Stress / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D014774:Virulence / Q000187:drug effects*; D037521:Virulence Factors / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D037521:Virulence Factors
keywords: DsbA inhibitors; DsbB inhibitors; anti-virulence; disulfide catalysis; fragment-based drug design, antimicrobial resistance