title: Apigenin as an anti-quinolone-resistance antibiotic.
abstract: We previously reported the first 'reverse antibiotic' (RA), nybomycin (NYB), which showed a unique antimicrobial activity against Staphylococcus aureus strains. NYB specifically suppressed the growth of quinolone-resistant S. aureus strains but was not effective against quinolone-susceptible strains. Although NYB was first reported in 1955, little was known about its unique antimicrobial activity because it was before the synthesis of the first quinolone ('old quinolone'), nalidixic acid, in 1962. Following our re-discovery of NYB, we looked for other RAs among natural substances that act on quinolone-resistant bacteria. Commercially available flavones were screened against S. aureus, including quinolone-resistant strains, and their minimum inhibitory concentrations (MICs) were compared using the microbroth dilution method. Some of the flavones screened showed stronger antimicrobial activity against quinolone-resistant strains than against quinolone-susceptible ones. Amongst them, apigenin (API) was the most potent in its RA activity. DNA cleavage assay showed that API inhibited DNA gyrase harbouring the quinolone resistance mutation gyrA(Ser84Leu) but did not inhibit 'wild-type' DNA gyrase that is sensitive to levofloxacin. An API-susceptible S. aureus strain Mu50 was also selected using agar plates containing 20mg/L API. Whole-genome sequencing of selected mutant strains was performed and frequent back-mutations (reverse mutations) were found among API-resistant strains derived from the API-susceptible S. aureus strains. Here we report that API represents another molecular class of natural antibiotic having RA activity against quinolone-resistant bacteria.
authors.affiliation: Center of Excellence for Infection Control Science, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Yuh
authors.initials: Y
authors.lastname: Morimoto
authors.affiliation: Center of Excellence for Infection Control Science, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Baba
authors.affiliation: Department of Bacteriology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Center of Excellence for Infection Control Science, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: khiram06@juntendo.ac.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hiramatsu
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology*; D001483:Base Sequence; D027081:DNA Gyrase / Q000235:genetics*; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D016680:Genome, Bacterial / Q000235:genetics; D006801:Humans; D064704:Levofloxacin / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D064704:Levofloxacin; D047310:Apigenin; D027081:DNA Gyrase; C005316:nybomycin
keywords: Apigenin; Nybomycin; Quinolone resistance; Reverse antibiotic; gyrA mutations