Journal
METALLOMICS
Volume 6, Issue 1, Pages 88-95Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3mt00125c
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Funding
- Swiss National Science Foundation [200021-116344, CR22I3_143770]
- State Secretariat for Education and Research [C11.0054]
- COST Actions [TD0905, CM0902]
- Holcim Foundation
- Novartis Foundation
- Swiss National Science Foundation (SNF) [CR22I3_143770] Funding Source: Swiss National Science Foundation (SNF)
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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.
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