title: Small-molecule inhibition of bacterial two-component systems to combat antibiotic resistance and virulence.
abstract: Infections caused by multidrug-resistant bacteria are a considerable and increasing global problem. The development of new antibiotics is not keeping pace with the rapid evolution of resistance to almost all clinically available drugs, and novel strategies are required to fight bacterial infections. One such strategy is the control of pathogenic behaviors, as opposed to simply killing bacteria. Bacterial two-component system (TCS) signal transduction pathways control many pathogenic bacterial behaviors, such as virulence, biofilm formation and antibiotic resistance and are, therefore, an attractive target for the development of new drugs. This review presents an overview of TCS that are potential targets for such a strategy, describes small-molecules inhibitors of TCS identified to date and discusses assays for the identification of novel inhibitors. The future perspective for the identification and use of inhibitors of TCS to potentially provide new therapeutic options for the treatment of drug-resistant bacterial infections is discussed.
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA.
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Worthington
authors.forename: Meghan S
authors.initials: MS
authors.lastname: Blackledge
authors.forename: Christian
authors.initials: C
authors.lastname: Melander
mesh_terms: D001419:Bacteria / Q000378:metabolism / Q000472:pathogenicity*; D001424:Bacterial Infections / Q000188:drug therapy; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D000071677:Histidine Kinase; D006801:Humans; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014774:Virulence / Q000187:drug effects*
chemical_list: D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D011494:Protein Kinases; D000071677:Histidine Kinase