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Issue 1, 2014
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Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibioticdrug design

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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 Zn2+-metallo-isoform of the enzyme, whereas the Mn2+-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.

Graphical abstract: Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibioticdrug design

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Publication details

The article was received on 16 Apr 2013, accepted on 08 Aug 2013 and first published on 08 Aug 2013


Article type: Paper
DOI: 10.1039/C3MT00125C
Citation: Metallomics, 2014,6, 88-95
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    Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: implications of metal heterogeneity for evolution and antibioticdrug design

    N. R. Uda, G. Upert, G. Angelici, S. Nicolet, T. Schmidt, T. Schwede and M. Creus, Metallomics, 2014, 6, 88
    DOI: 10.1039/C3MT00125C

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