Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibiotic drug design.
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.
University of Basel, Department of Chemistry, Spitalstrasse 51, Basel 4056, Switzerland. marc.creus@unibas.ch.
Narasimha Rao
NR
Uda
Grégory
G
Upert
Gaetano
G
Angelici
Stefan
S
Nicolet
Tobias
T
Schmidt
Torsten
T
Schwede
Marc
M
Creus
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D002216:Captopril / Q000737:chemistry / Q000494:pharmacology*; D003960:Diaminopimelic Acid / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology; D008667:Metalloproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D019779:Salmonella enterica / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry* / Q000494:pharmacology
D000581:Amidohydrolases; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002216:Captopril; D003960:Diaminopimelic Acid; D007527:Isoenzymes; D008345:Manganese; D008667:Metalloproteins; D013438:Sulfhydryl Compounds; D015032:Zinc; C054685:N-succinyl-l,l-diaminopimelic acid desuccinylase