An inhibitor of FtsZ with potent and selective anti-staphylococcal activity

被引：389

作者：

Haydon, David J. ^{[1
]}

Stokes, Neil R. ^{[1
]}

Ure, Rebecca ^{[1
]}

Galbraith, Greta ^{[1
]}

Bennett, James M. ^{[1
]}

Brown, David R. ^{[1
]}

Baker, Patrick J. ^{[2
]}

Barynin, Vladimir V. ^{[2
]}

Rice, David W. ^{[2
]}

Sedelnikova, Sveta E. ^{[2
]}

Heal, Jonathan R. ^{[3
]}

Sheridan, Joseph M. ^{[3
]}

Aiwale, Sachin T. ^{[4
]}

Chauhan, Pramod K. ^{[4
]}

Srivastava, Anil ^{[4
]}

Taneja, Amit ^{[4
]}

Collins, Ian ^{[1
]}

Errington, Jeff ^{[1
,5
]}

Czaplewski, Lloyd G. ^{[1
]}

机构：

[1] Prolysis, Oxford OX5 1PF, England

[2] Univ Sheffield, Dept Mol Biol & Biotechnol, Sheffield S10 2TN, S Yorkshire, England

[3] Prosarix, Cambridge CB22 7ZE, England

[4] Jubilant Chemsys, Noida 201301, India

[5] Univ Newcastle, Fac Med Sci, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

来源：

SCIENCE | 2008年 / 321卷 / 5896期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1126/science.1159961

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi- drug- resistant Staphylococcus aureus. The putative inhibitor- binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol- binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti- staphylococcal therapy.

引用

页码：1673 / 1675

页数：3

共 17 条

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