title: Studies on the antimicrobial properties of N-acylated ciprofloxacins.
abstract: Fluoroquinolone antibiotics have been a mainstay in the treatment of bacterial diseases. The most notable representative, ciprofloxacin, possesses potent antimicrobial activity; however, a rise in resistance to this agent necessitates development of novel derivatives to prolong the clinical lifespan of these antibiotics. Herein we have synthesized and analyzed the antimicrobial properties of a library of N-acylated ciprofloxacin analogues. We find that these compounds are broadly effective against Gram-positive and Gram-negative bacteria, with many proving more effective than the parental drug, and several possessing MICs ≤1.0 μg/ml against methicillin-resistant Staphylococcus aureus and Bartonella species. An analysis of spontaneous mutation frequencies reveals very low potential for resistance in MRSA compared to existing fluoroquinolones. Mode of action profiling reveals that modification of the piperazinyl nitrogen by acylation does not alter the effect of these molecules towards their bacterial target. We also present evidence that these N-acylated compounds are highly effective at killing intracellular bacteria, suggesting the suitability of these antibiotics for therapeutic treatment.
authors.affiliation: Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Cormier
authors.forename: Whittney N
authors.initials: WN
authors.lastname: Burda
authors.forename: Lacey
authors.initials: L
authors.lastname: Harrington
authors.forename: Jordan
authors.initials: J
authors.lastname: Edlinger
authors.forename: Karthik M
authors.initials: KM
authors.lastname: Kodigepalli
authors.forename: John
authors.initials: J
authors.lastname: Thomas
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kapolka
authors.forename: Glen
authors.initials: G
authors.lastname: Roma
authors.forename: Burt E
authors.initials: BE
authors.lastname: Anderson
authors.forename: Edward
authors.initials: E
authors.lastname: Turos
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Shaw
mesh_terms: D000215:Acylation; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy; D001473:Bartonella / Q000187:drug effects; D001474:Bartonella Infections / Q000188:drug therapy; D002939:Ciprofloxacin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin