title: Kibdelomycin is a bactericidal broad-spectrum aerobic antibacterial agent.
abstract: Bacterial resistance to antibiotics continues to grow and pose serious challenges, while the discovery rate for new antibiotics declines. Kibdelomycin is a recently discovered natural-product antibiotic that inhibits bacterial growth by inhibiting the bacterial DNA replication enzymes DNA gyrase and topoisomerase IV. It was reported to be a broad-spectrum aerobic Gram-positive agent with selective inhibition of the anaerobic bacterium Clostridium difficile. We have extended the profiling of kibdelomycin by using over 196 strains of Gram-positive and Gram-negative aerobic pathogens recovered from worldwide patient populations. We report the MIC50s, MIC90s, and bactericidal activities of kibdelomycin. We confirm the Gram-positive spectrum and report for the first time that kibdelomycin shows strong activity (MIC90, 0.125 μg/ml) against clinical strains of the Gram-negative nonfermenter Acinetobacter baumannii but only weak activity against Pseudomonas aeruginosa. We confirm that well-characterized resistant strains of Staphylococcus aureus and Streptococcus pneumoniae show no cross-resistance to kibdelomycin and quinolones and coumarin antibiotics. We also show that kibdelomycin is not subject to efflux in Pseudomonas, though it is in Escherichia coli, and it is generally affected by the outer membrane permeability entry barrier in the nonfermenters P. aeruginosa and A. baumannii, which may be addressable by structure-based chemical modification.
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA sheo.singh.215@gmail.com.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Dayananth
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Balibar
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Garlisi
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kishii
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takei
authors.affiliation: Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D011758:Pyrroles; D011760:Pyrrolidinones; C000601708:kibdelomycin
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