Discovery of a Small Molecule That Inhibits Cell Division by Blocking FtsZ, a Novel Therapeutic Target of Antibiotics

The emergence of bacterial resistance to antibiotics is a major health problem and, therefore, it is critical to develop new antibiotics with novel modes of action. FtsZ, a tubulin-like GTPase, plays an essential role in bacterial cell division, and its homologs are present in almost all eubacteria...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2003-11, Vol.278 (45), p.44424-44428
Main Authors: Wang, Jun, Galgoci, Andrew, Kodali, Srinivas, Herath, Kithsiri B., Jayasuriya, Hiranthi, Dorso, Karen, Vicente, Francisca, González, Antonio, Cully, Doris, Bramhill, David, Singh, Sheo
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - isolation & purification
Anti-Bacterial Agents - pharmacology
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Bacterial Proteins - physiology
Cell Division - drug effects
Cytoskeletal Proteins
Drug Resistance, Microbial
Enterococcus faecium - drug effects
Escherichia coli - drug effects
Fluorescein
Fluorescent Dyes
FtsZ protein
GTP Phosphohydrolases - antagonists & inhibitors
GTP Phosphohydrolases - metabolism
Guanosine Triphosphate - metabolism
Guanosine Triphosphate - pharmacology
Hydrolysis
Kinetics
Microbial Sensitivity Tests
Molecular Structure
Naphthols - chemistry
Naphthols - isolation & purification
Naphthols - pharmacology
Polymers - chemistry
Staphylococcus aureus
Staphylococcus aureus - drug effects
Streptococcus pneumoniae - drug effects
viriditoxin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The emergence of bacterial resistance to antibiotics is a major health problem and, therefore, it is critical to develop new antibiotics with novel modes of action. FtsZ, a tubulin-like GTPase, plays an essential role in bacterial cell division, and its homologs are present in almost all eubacteria and archaea. During cell division, FtsZ forms polymers in the presence of GTP that recruit other division proteins to make the cell division apparatus. Therefore, inhibition of FtsZ polymerization will prevent cells from dividing, leading to cell death. Using a fluorescent FtsZ polymerization assay, the screening of >100,000 extracts of microbial fermentation broths and plants followed by fractionation led to the identification of viriditoxin, which blocked FtsZ polymerization with an IC50 of 8.2 μg/ml and concomitant GTPase inhibition with an IC50 of 7.0 μg/ml. That the mode of antibacterial action of viriditoxin is via inhibition of FtsZ was confirmed by the observation of its effects on cell morphology, macromolecular synthesis, DNA-damage response, and increased minimum inhibitory concentration as a result of an increase in the expression of the FtsZ protein. Viriditoxin exhibited broad-spectrum antibacterial activity against clinically relevant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci, without affecting the viability of eukaryotic cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M307625200