title: In vitro and in vivo antipseudomonal activity, acute toxicity, and mode of action of a newly synthesized fluoroquinolonyl ampicillin derivative.
abstract: Compounds N-(6,7-difluoroquinolonyl)-ampicillin (AU-1) and N-(6-fluoroquinolonyl)-ampicillin (FQ-1), synthesized by coupling of the carboxyl group of 6,7-difluoroquinolone (FP-3) and 6-fluoroquinolone (FP4), respectively, with the alpha-amino-group of ampicillin side chain, exhibit antipseudomonal activity similar to and lower acute toxicity than that of norfloxacin, whereas neither ampicillin nor the fluoroquinolone moieties, compound FP-3 or FP4, alone have such activity. Also, AU-1 and FQ-1 are active against tested clinical isolates of Pseudomonas aeruginosa that are highly resistant to norfloxacin, gentamicin, or both. The therapeutic efficacies of FQ-1 and norfloxacin were assessed and compared in neutropenic mice infected with a 90% lethal dose of P aeruginosa. Mice intraperitoneally administered FQ-1 (10 mg/kg) 4, 8, 24, and 48 hours after infection had survival rates as high as 80%, comparable to those of mice treated with norfloxacin at the same dosage and dosing schedule. The study of protoplast formation revealed that FQ-1 did not inhibit cell-wall biosynthesis but did induce cell filamentation of Bacillus subtilis at a level close to its minimal inhibition concentration. Both AU-1 and FQ-1 were able to intercalate into the double-stranded DNA. However, that FQ-1 lost such activity after it was treated with penicillinase suggests that the lactam-ring structure in ampicillin moiety of FQ-1 was hydrolyzed by penicillinase and that the hydrolyzed structure of FQ-1 does not own DNA-intercalation activity.
authors.affiliation: Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Wen-Po
authors.initials: WP
authors.lastname: Lin
authors.forename: Dar-Der
authors.initials: DD
authors.lastname: Ji
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Shiau
authors.forename: Tse-Chun
authors.initials: TC
authors.lastname: Yang
authors.forename: Yung-Wen
authors.initials: YW
authors.lastname: Yang
authors.forename: Tai-Li
authors.initials: TL
authors.lastname: Tsou
authors.forename: Shang-Tao
authors.initials: ST
authors.lastname: Tang
authors.forename: Chi-Hsing
authors.initials: CH
authors.lastname: Chen
authors.forename: Yu-Tien
authors.initials: YT
authors.lastname: Liu
mesh_terms: D000667:Ampicillin / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D066298:In Vitro Techniques; D051379:Mice; D010406:Penicillins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010957:Plasmids; D011523:Protoplasts / Q000187:drug effects; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
chemical_list: D010406:Penicillins; D000667:Ampicillin