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<sup>2+</sup>-metallo-isoform of the enzyme, whereas the Mn <sup>2+</sup>-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. © 2014 The Royal Society of Chemistry.

Zinc-selective inhibition of the promiscuous bacterial amide-hydrolase DapE: Implications of metal heterogeneity for evolution and antibiotic drug design

ANGELICI, GAETANO;
2014-01-01

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 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. © 2014 The Royal Society of Chemistry.
2014
Uda, Narasimha Rao; Upert, Grégory; Angelici, Gaetano; Nicolet, Stefan; Schmidt, Tobias; Schwede, Torsten; Creus, Marc
File in questo prodotto:
File Dimensione Formato  
Uda_etal13_Metallomics_Creus.pdf

accesso aperto

Descrizione: Open Access Article
Tipologia: Versione finale editoriale
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.57 MB
Formato Adobe PDF
1.57 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/837847
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 21
social impact