Development of Des-Fatty Acyl-Polymyxin B Decapeptide Analogs with Pseudomonas aeruginosa-Specific Antimicrobial Activity

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概要

• 論文の詳細を見る

• Twelve N-terminal analogs of des-fatty acyl-polymyxin B (Des-FA-[X^1]-PMB, X=various amino acids or peptides) were synthesized and examined for their antimicrobial activity against Escherichia coli (E. coli), Salmonella Typhimurium (S. Typhimurium) and Pseudomonas aeruginosa (P. aeruginosa). It was found that Des-FA-[Dap^1]-, Des-FA-[Ser^1]-, Des-FA-[Dab-Dab-Dab^1]- and Des-FA-[Arg-Arg-Arg^1]-PMB had potent activity only against P. aeruginosa, with MIC values of 0.5-1nmol/ml. Analogs in which X was Lys, Arg, Leu or Ala did not have increased antimicrobial activity against the three bacterial species tested compared with the lead compounds Des-FA-[Dab^1]-PMB and polymyxin B (PMB). Des-FA-[Trp^1]-PMB and Des-FA-[Phe^1]-PMB had reduced activity against P. aeruginosa. The results indicate that compact hydrophilic amino acids (C3) or basic tripeptides at the N-terminal provide specificity for bactericidal activity towards P. aeruginosa. For LPS-binding activity, Des-FA-[Dab-Dab-Dab^1]-PMB and Des-FA-[Arg-Arg-Arg^1]-PMB showed activity comparable to PMB, while Des-FA-[Ala-Ala-Ala^1]-PMB showed very low activity. Reduced acute toxicity of Des-FA-[Dap^1]-PMB and Des-FA-[Trp^1]-PMB was demonstrated by a mouse tail intravenous administration test, with LD_<50> values of 23.5 and 19.0μmol/kg, respectively, in contrast to PMB (LD_<50>, 4.8μmol/kg).

• 社団法人日本薬学会の論文
• 2009-04-01

著者

• SATO Yuki

  Faculty of Agriculture, Niigata University

• Sato Y

  Faculty Of Pharmaceutical Sciences Hokuriku University

• Sato Y

  Division Of Organic Chemistry National Institute Of Health Sciences

• KATSUMA Naoko

  Faculty of Pharmaceutical Sciences, Hokuriku University

• OHKI Kazuhiro

  Faculty of Pharmaceutical Sciences, Hokuriku University

• OKIMURA Keiko

  Faculty of Pharmaceutical Sciences, Hokuriku University

• OHNISHI Kuniharu

  Faculty of Pharmaceutical Sciences, Hokuriku University

• SAKURA Naoki

  Faculty of Pharmaceutical Sciences, Hokuriku University

• Ohnishi Kuniharu

  Faculty Of Pharmaceutical Sciences Hokuriku University

• Ohnishi Kuniharu

  北陸大学 薬学部

• Katsuma Naoko

  Faculty Of Pharmaceutical Sciences Hokuriku University

• Ohki K

  Faculty Of Pharmaceutical Sciences Hokuriku University

• Ohki Kazuhiro

  北陸大学 薬学部

• Ohki Kazuhiro

  Faculty Of Pharmaceutical Sciences Hokuriku University

• Okimura K

  Faculty Of Pharmaceutical Sciences Hokuriku University

• Okimura Keiko

  北陸大学 薬学部

• Okimura Keiko

  Faculty Of Pharmaceutical Sciences Hokuriku University

• 佐倉 直樹

  北陸大・薬

• Sakura N

  Hokuriku Univ. Kanazawa Jpn

• Sakura Naoki

  北陸大学 薬 生物活性

• Sakura Naoki

  北陸大学 薬学部

• Sakura Naoki

  Faculty Of Pharmaceutical Sciences Hokuriku University

• Sato Yukiko

  Division Of Organic Chemistry National Institute Of Health Sciences

• Sato Yuki

  Faculty Of Agriculture Niigata University

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