ABSTRACT
Fosmidomycin inhibits IspC (1-deoxy-d-xylulose 5-phosphate reductoisomerase), the first committed enzyme in the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis. The MEP pathway of isoprenoid biosynthesis is essential to the causative agent of the plague, Yersinia pestis, and is entirely distinct from the corresponding mammalian pathway. To further drug development, we established structure-activity relationships of fosmidomycin analogues by assessing a suite of 17 α-phenyl-substituted reverse derivatives of fosmidomycin against Y. pestis IspC. Several of these compounds showed increased potency over fosmidomycin with IC50 values in the nanomolar range. Additionally, we performed antimicrobial susceptibility testing with Y. pestis A1122 (YpA1122). The bacteria were susceptible to several compounds with minimal inhibitory concentration (MIC) values ranging from 128 to 512 µg/mL; a correlation between the IC50 and MIC values was observed.
ABSTRACT
1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (PfIspC, PfDxr), believed to be the rate-limiting enzyme of the nonmevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. To gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-methoxyphenyl substituted derivative 2c showed potent inhibition of PfIspC as well as of P. falciparum growth and was more than one order of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex with PfIspC, reduced nicotinamide adenine dinucleotide phosphate, and Mg(2+) were determined by X-ray structure analysis. Notably, PfIspC selectively binds the S-enantiomers of the study compounds.
Subject(s)
Aldose-Ketose Isomerases/antagonists & inhibitors , Fosfomycin/analogs & derivatives , Aldose-Ketose Isomerases/metabolism , Catalytic Domain , Crystallization , Fosfomycin/chemical synthesis , Fosfomycin/pharmacology , NADP/metabolism , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Structure-Activity RelationshipABSTRACT
The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of "reverse" thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative.
Subject(s)
Aldose-Ketose Isomerases/antagonists & inhibitors , Anti-Infective Agents/pharmacology , Drug Discovery/methods , Fosfomycin/analogs & derivatives , Aldose-Ketose Isomerases/genetics , Aldose-Ketose Isomerases/metabolism , Amino Acid Sequence , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Crystallography, X-Ray , Escherichia coli/drug effects , Escherichia coli/enzymology , Escherichia coli/genetics , Fosfomycin/chemical synthesis , Fosfomycin/chemistry , Fosfomycin/pharmacology , Models, Chemical , Models, Molecular , Molecular Sequence Data , Molecular Structure , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/genetics , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Plasmodium falciparum/genetics , Protein Binding , Protein Structure, Tertiary , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Sequence Homology, Amino Acid , StereoisomerismABSTRACT
Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.
