title: Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.
abstract: Vancomycin is mainly used as an antibacterial agent of last resort, but recently vancomycin-resistant bacterial strains have been emerging. Although new antimicrobials have been developed in order to overcome drug-resistant bacteria, many are structurally complex beta-lactams or quinolones. In this study, we aimed to create new anti-drug-resistance antibacterials which can be synthesized in a few steps from inexpensive starting materials. Since sulfa drugs function as p-aminobenzoic acid mimics and inhibit dihydropteroate synthase (DHPS) in the folate pathway, we hypothesized that sulfa derivatives would act as folate metabolite-mimics and inhibit bacterial folate metabolism. Screening of our sulfonanilide libraries, including benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors, led us to discover benzenesulfonanilides with potent anti-methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant Enterococcus (VRE) activity, that is, N-3,5-bis(trifluoromethyl)phenyl-3,5-dichlorobenzenesulfonanilide (16b) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl)benzenesulfonanilide (16c) [MIC=0.5microg/mL (MRSA), 1.0microg/mL (VRE)]. These compounds are more active than vancomycin [MIC=2.0microg/mL (MRSA), 125microg/mL (VRE)], but do not possess an amino group, which is essential for DHPS inhibition by sulfa drugs. These results suggested that the mechanism of antibacterial action of compounds 16b and 16c is different from that of sulfa drugs. We also confirmed the activity of these compounds against clinical isolates of Gram-positive bacteria.
authors.affiliation: Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Namba
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zheng
authors.forename: Kazunori
authors.initials: K
authors.lastname: Motoshima
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tai
authors.forename: Eizo
authors.initials: E
authors.lastname: Takahashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasaki
authors.forename: Keinosuke
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D015195:Drug Design; D016984:Enterococcus faecium / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D016106:Methicillin Resistance; D051379:Mice; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D020713:Vancomycin Resistance
chemical_list: D000813:Anilides; D000900:Anti-Bacterial Agents; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D013449:Sulfonamides; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse