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
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
收藏
页码:1673 / 1675
页数:3
相关论文
共 17 条
[11]   Preclinical evaluation of novel antibacterial agents by microbiological and molecular techniques [J].
O'Neill, AJ ;
Chopra, I .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2004, 13 (08) :1045-1063
[12]   The lethal effect of a benzamide derivative, 3-methoxybenzamide, can be suppressed by mutations within a cell division gene, ftsZ, in Bacillus subtilis [J].
Ohashi, Y ;
Chijiiwa, Y ;
Suzuki, K ;
Takahashi, K ;
Nanamiya, H ;
Sato, T ;
Hosoya, Y ;
Ochi, K ;
Kawamura, F .
JOURNAL OF BACTERIOLOGY, 1999, 181 (04) :1348-1351
[13]   Structural insights into the conformational variability of FtsZ [J].
Oliva, Maria A. ;
Trambaiolo, Daniel ;
Loewe, Jan .
JOURNAL OF MOLECULAR BIOLOGY, 2007, 373 (05) :1229-1242
[14]   Parallel solid synthesis of inhibitors of the essential cell division FtsZ enzyme as a new potential class of antibacterials [J].
Paradis-Bleau, Catherine ;
Beaumont, Melanie ;
Sanschagrin, Francois ;
Voyer, Normand ;
Levesque, Roger C. .
BIOORGANIC & MEDICINAL CHEMISTRY, 2007, 15 (03) :1330-1340
[15]   Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay [J].
Stokes, NR ;
Sievers, J ;
Barker, S ;
Bennett, JM ;
Brown, DR ;
Collins, I ;
Errington, VM ;
Foulger, D ;
Hall, M ;
Halsey, R ;
Johnson, H ;
Rose, V ;
Thomaides, HB ;
Haydon, DJ ;
Czaplewski, LG ;
Errington, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (48) :39709-39715
[16]   The prokaryotic cytoskeleton: a putative target for inhibitors and antibiotics? [J].
Vollmer, Waldemar .
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY, 2006, 73 (01) :37-47
[17]   Discovery of a small molecule that inhibits cell division by blocking FtsZ, a novel therapeutic target of antibiotics [J].
Wang, J ;
Galgoci, A ;
Kodali, S ;
Herath, KB ;
Jayasuriya, H ;
Dorso, K ;
Vicente, F ;
González, A ;
Cully, D ;
Bramhill, D ;
Singh, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (45) :44424-44428