Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus

Kensuke Namba, Xiaoxia Zheng, Kazunori Motoshima, Hidetomo Kobayashi, Akihiro Tai, Eizo Takahashi, Kenji Sasaki, Keinosuke Okamoto, Hiroki Kakuta

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 β-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 = 0.5 μg/mL (MRSA), 1.0 μg/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl)benzenesulfonanilide (16c) [MIC = 0.5 μg/mL (MRSA), 1.0 μg/mL (VRE)]. These compounds are more active than vancomycin [MIC = 2.0 μg/mL (MRSA), 125 μg/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.

Original languageEnglish
Pages (from-to)6131-6144
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number11
DOIs
Publication statusPublished - Jun 1 2008

Fingerprint

Methicillin
Vancomycin
Methicillin-Resistant Staphylococcus aureus
Dihydropteroate Synthase
Folic Acid
Pharmaceutical Preparations
Bacterial Drug Resistance
4-Aminobenzoic Acid
Lactams
Cyclooxygenase 1
Quinolones
Gram-Positive Bacteria
Bacteria
Libraries
Anti-Bacterial Agents
Metabolites
Vancomycin-Resistant Enterococci
Metabolism
Screening
Derivatives

Keywords

  • Anti-MRSA
  • Anti-VRE
  • Benzenesulfonanilides
  • Methicillin-resistant Staphylococcus aureus
  • Sulfa drugs
  • Vancomycin-resistant Enterococcus

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. / Namba, Kensuke; Zheng, Xiaoxia; Motoshima, Kazunori; Kobayashi, Hidetomo; Tai, Akihiro; Takahashi, Eizo; Sasaki, Kenji; Okamoto, Keinosuke; Kakuta, Hiroki.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 11, 01.06.2008, p. 6131-6144.

Research output: Contribution to journalArticle

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