title: Combating drug-resistant bacteria: small molecule mimics of plasmid incompatibility as antiplasmid compounds.
abstract: A major mechanism for bacterial resistance to antibiotics is through the acquisition of a plasmid coding for resistance-mediating proteins. Described herein is a strategy to eliminate these plasmids from bacteria, thus resensitizing the bacteria to antibiotics. This approach involves mimicking a natural mechanism for plasmid elimination, known as plasmid incompatibility. The compound apramycin was identified as a tight binder to SLI RNA (Kd = 93 nM), the in vivo target of the plasmid incompatibility determinate RNA I, and footprinting/mutagenesis studies indicate apramycin binds SLI in the important regulatory region that dictates plasmid replication control and incompatibility. In vivo studies demonstrate that this compound causes significant plasmid loss and resensitizes bacteria to conventional antibiotics. The demonstration that a small molecule can mimic incompatibility, cause plasmid elimination, and resensitize bacteria to antibiotics opens up new targets for antibacterial research.
authors.affiliation: Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Johna C B
authors.initials: JC
authors.lastname: Denap
authors.forename: Jason R
authors.initials: JR
authors.lastname: Thomas
authors.forename: Dinty J
authors.initials: DJ
authors.lastname: Musk
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D040761:Biomimetic Materials / Q000378:metabolism / Q000494:pharmacology; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D009328:Nebramycin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D011815:R Factors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D001618:beta-Lactamases / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; D015534:Trans-Activators; C045264:replication initiator protein; D009328:Nebramycin; C011666:apramycin; D001618:beta-Lactamases; D004265:DNA Helicases