Publication Date:
2008-09-20
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haydon, David J -- Stokes, Neil R -- Ure, Rebecca -- Galbraith, Greta -- Bennett, James M -- Brown, David R -- Baker, Patrick J -- Barynin, Vladimir V -- Rice, David W -- Sedelnikova, Sveta E -- Heal, Jonathan R -- Sheridan, Joseph M -- Aiwale, Sachin T -- Chauhan, Pramod K -- Srivastava, Anil -- Taneja, Amit -- Collins, Ian -- Errington, Jeff -- Czaplewski, Lloyd G -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2008 Sep 19;321(5896):1673-5. doi: 10.1126/science.1159961.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Prolysis, Begbroke Science Park, Oxfordshire OX5 1PF, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18801997" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Anti-Bacterial Agents/*pharmacology/therapeutic use
;
Bacillus subtilis/chemistry/*drug effects/genetics
;
Bacterial Proteins/*antagonists & inhibitors/chemistry/genetics/metabolism
;
Binding Sites
;
Cell Division/drug effects
;
Crystallography, X-Ray
;
Cytoskeletal Proteins/*antagonists & inhibitors/chemistry/genetics/metabolism
;
Drug Resistance, Bacterial/genetics
;
Drug Resistance, Multiple, Bacterial
;
Ligands
;
Methicillin Resistance
;
Mice
;
Microbial Sensitivity Tests
;
Models, Molecular
;
Molecular Sequence Data
;
Mutation
;
Protein Conformation
;
Pyridines/chemistry/metabolism/*pharmacology/therapeutic use
;
Staphylococcal Infections/*drug therapy
;
Staphylococcus aureus/chemistry/*drug effects
;
Thiazoles/chemistry/metabolism/*pharmacology/therapeutic use
;
Tubulin/chemistry/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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