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 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 microg/ml and concomitant GTPase inhibition with an IC50 of 7.0 microg/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.
Wang
Jun
J
Department of Human and Animal Infectious Disease, Merck Research Laboratories, Rahway, New Jersey 07065, USA. jun_wang2@merck.com
Galgoci
Andrew
A
Kodali
Srinivas
S
Herath
Kithsiri B
KB
Jayasuriya
Hiranthi
H
Dorso
Karen
K
Vicente
Francisca
F
González
Antonio
A
Cully
Doris
D
Bramhill
David
D
Singh
Sheo
S
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D002455:Cell Division / Q000187:drug effects*; D003598:Cytoskeletal Proteins; D004352:Drug Resistance, Microbial; D016984:Enterococcus faecium / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D019793:Fluorescein; D005456:Fluorescent Dyes; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D006868:Hydrolysis; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; D005456:Fluorescent Dyes; C071525:FtsZ protein, Bacteria; D009284:Naphthols; D011108:Polymers; C010375:viriditoxin; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D019793:Fluorescein