Abstract
1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-negative bacteria. A coordination chemistry and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC(50) of 1.4 microM. It exhibited a broad spectrum of activity against Gram-negative and -positive bacteria with minimal inhibition concentrations of 20-100 microM (or 3.7-19 microg/mL).
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aldose-Ketose Isomerases / antagonists & inhibitors*
-
Aldose-Ketose Isomerases / chemistry*
-
Anti-Bacterial Agents / chemical synthesis*
-
Anti-Bacterial Agents / chemistry
-
Anti-Bacterial Agents / pharmacology
-
Cell Line
-
Cell Membrane Permeability
-
Chelating Agents / chemical synthesis*
-
Chelating Agents / chemistry
-
Chelating Agents / pharmacology
-
Drug Resistance, Bacterial
-
Fosfomycin / analogs & derivatives
-
Fosfomycin / chemistry
-
Fosfomycin / pharmacology
-
Gram-Negative Bacteria / drug effects
-
Gram-Positive Bacteria / drug effects
-
Humans
-
Magnesium / chemistry*
-
Microbial Sensitivity Tests
-
Models, Molecular
-
Multienzyme Complexes / antagonists & inhibitors*
-
Multienzyme Complexes / chemistry*
-
Oxidoreductases / antagonists & inhibitors*
-
Oxidoreductases / chemistry*
-
Pyridones / chemical synthesis*
-
Pyridones / chemistry
-
Pyridones / pharmacology
-
Structure-Activity Relationship
Substances
-
Anti-Bacterial Agents
-
Chelating Agents
-
Multienzyme Complexes
-
Pyridones
-
Fosfomycin
-
fosmidomycin
-
Oxidoreductases
-
1-deoxy-D-xylulose 5-phosphate reductoisomerase
-
Aldose-Ketose Isomerases
-
Magnesium