title: Small molecule downregulation of PmrAB reverses lipid A modification and breaks colistin resistance.
abstract: Infections caused by multi-drug resistant bacteria, particularly Gram-negative bacteria, are an ever-increasing problem. While the development of new antibiotics remains one option in the fight against bacteria that have become resistant to currently available antibiotics, an attractive alternative is the development of adjuvant therapeutics that restore the efficacy of existing antibiotics. We report a small molecule adjuvant that suppresses colistin resistance in multidrug resistant Acinetobacter baumannii and Klebsiella pneumoniae by interfering with the expression of a two-component system. The compound downregulates the pmrCAB operon and reverses phosphoethanolamine modification of lipid A responsible for colistin resistance. Furthermore, colistin-susceptible and colistin-resistant bacteria do not evolve resistance to combination treatment. This represents the first definitive example of a compound that breaks antibiotic resistance by directly modulating two-component system activity.
authors.affiliation: Department of Chemistry, North Carolina State University , Raleigh, North Carolina 27695, United States.
authors.forename: Tyler L
authors.initials: TL
authors.lastname: Harris
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Worthington
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Hittle
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Zurawski
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.forename: Christian
authors.initials: C
authors.lastname: Melander
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D003091:Colistin / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008050:Lipid A / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008050:Lipid A; C409039:PmrB protein, bacteria; D054852:Small Molecule Libraries; D014157:Transcription Factors; C081902:pmrA protein, Bacteria; D003091:Colistin