Discovery of MC-02,331, a new cephalosporin exhibiting potent activity against methicillin-resistant Staphylococcus aureus

被引：18

作者：

Hecker, SJ ^{[1
]}

Cho, IS ^{[1
]}

Glinka, TW ^{[1
]}

Zhang, ZJ ^{[1
]}

Price, ME ^{[1
]}

Lee, VJ ^{[1
]}

Christensen, BG ^{[1
]}

Boggs, A ^{[1
]}

Chamberland, S ^{[1
]}

Malouin, F ^{[1
]}

Parr, TR ^{[1
]}

Annamalai, T ^{[1
]}

Blais, J ^{[1
]}

Bond, EL ^{[1
]}

Case, L ^{[1
]}

Chan, C ^{[1
]}

Crase, J ^{[1
]}

Frith, R ^{[1
]}

Griffith, D ^{[1
]}

Harford, L ^{[1
]}

Liu, N ^{[1
]}

Ludwikow, M ^{[1
]}

Mathias, K ^{[1
]}

Rea, D ^{[1
]}

Williams, R ^{[1
]}

机构：

[1] Microcide Pharmaceut Inc, Mt View, CA 94043 USA

来源：

JOURNAL OF ANTIBIOTICS | 1998年 / 51卷 / 08期

关键词：

D O I：

10.7164/antibiotics.51.722

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

A systematic approach toward building activity against methicillin-resistant staphylococci into the cephalosporin class of beta-lactam antibiotics is described. Initial work focused on finding the optimal linkage between the cephem nucleus and a biphenyl pharmacophore, which established that a thio linkage,afforded potent activity in vitro. Efforts to optimize this activity by altering substitution on the pharmacophore afforded iodophenylthio analog MC-02,002, which although highly potent against MRSA, was also highly bound to serum proteins. Further work to decrease serum protein binding showed that replacement of the iodo substituent by the positively-charged isothiouronium group afforded potent activity and reduced serum binding, but insufficient aqueous solubility. Solubility was enhanced by incorporation of a second positively-charged group into the 7-acyl substituent. Such derivatives (MC-02,171 and MC-02,306) lacked sufficient stability to staphylococcal beta-lactamase enzymes. The second positive charge was incorporated into the cephem 3-substituent in order to utilize the beta-lactamase-stable aminothiazolyl(oximino)acetyl class of 7-substituents. These efforts culminated with the discovery of bis(isothiouroniummethyl)phenylthio analog MC-02,331, whose profile is acceptable with respect to potency against MRSA, serum binding, aqueous solubility, and beta-lactamase stability.

引用

页码：722 / 734

页数：13

共 15 条

[1]

[Anonymous], 1993, M7A3 NCCLS

[2] Methicillin resistance in staphylococci: Molecular and biochemical basis and clinical implications [J].