Abstract
The development of resistance to virtually all current antibiotics makes the discovery of new antimicrobial compounds with novel protein targets an urgent challenge. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is an essential metallo-enzyme for growth and proliferation in many bacteria, acting in the desuccinylation of N-succinyl-L,L-diaminopimelic acid (SDAP) in a late stage of the anabolic pathway towards both lysine and a crucial building block of the peptidoglycan cell wall. L-Captopril, which has been shown to exhibit very promising inhibitory activity in vitro against DapE and has attractive drug-like properties, nevertheless does not target DapE in bacteria effectively. Here we show that L-captopril targets only the Zn(2+)-metallo-isoform of the enzyme, whereas the Mn(2+)-enzyme, which is also a physiologically relevant isoform in bacteria, is not inhibited. Our finding provides a rationale for the failure of this promising lead-compound to exhibit any significant antibiotic activity in bacteria and underlines the importance of addressing metallo-isoform heterogeneity in future drug design. Moreover, to our knowledge, this is the first example of metallo-isoform heterogeneity in vivo that provides an evolutionary advantage to bacteria upon drug-challenge.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amidohydrolases / antagonists & inhibitors*
-
Amidohydrolases / chemistry
-
Amidohydrolases / metabolism
-
Anti-Bacterial Agents / chemistry
-
Anti-Bacterial Agents / pharmacology
-
Bacterial Proteins / antagonists & inhibitors*
-
Bacterial Proteins / chemistry
-
Bacterial Proteins / metabolism
-
Binding Sites
-
Biocatalysis / drug effects
-
Captopril / chemistry
-
Captopril / pharmacology*
-
Diaminopimelic Acid / chemistry
-
Diaminopimelic Acid / metabolism
-
Dose-Response Relationship, Drug
-
Drug Design
-
Drug Resistance, Bacterial / drug effects
-
Isoenzymes / antagonists & inhibitors
-
Isoenzymes / chemistry
-
Isoenzymes / metabolism
-
Kinetics
-
Manganese / chemistry
-
Manganese / pharmacology
-
Metalloproteins / antagonists & inhibitors
-
Metalloproteins / chemistry
-
Metalloproteins / metabolism
-
Models, Molecular
-
Molecular Structure
-
Protein Structure, Tertiary
-
Salmonella enterica / drug effects
-
Salmonella enterica / enzymology
-
Salmonella enterica / growth & development
-
Sulfhydryl Compounds / chemistry
-
Sulfhydryl Compounds / metabolism
-
Zinc / chemistry*
-
Zinc / pharmacology
Substances
-
Anti-Bacterial Agents
-
Bacterial Proteins
-
Isoenzymes
-
Metalloproteins
-
Sulfhydryl Compounds
-
Manganese
-
Diaminopimelic Acid
-
Captopril
-
Amidohydrolases
-
succinyldiaminopimelate desuccinylase
-
Zinc