An Update on the Status of Potent Inhibitors of Metallo-β-Lactamases

Faridoon,; Islam, Nazar Ul

doi:10.3797/scipharm.1302-08

Cited by 21 publications

(14 citation statements)

References 61 publications

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“…Some of these enzymes employ very similar metal coordination arrangement as observed for hETHE1. Such enzymes include MBLs themselves ( 46 ) in efforts to combat antibiotic resistance and, e.g. the iron and 2OG oxygenases, e.g.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy

Pettinati

Brem

McDonough

et al. 2015

Human Molecular Genetics

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The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron binding member of the metallo-β-lactamase (MBL) fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 Å resolution. hETHE1 contains an αββα MBL-fold, which supports metal-binding by the side chains of an aspartate and two histidine residues; three water molecules complete octahedral coordination of the iron. The iron binding hETHE1 enzyme is related to the ‘classical’ di-zinc binding MBL hydrolases involved in antibiotic resistance, but has distinctive features. The histidine and aspartate residues involved in iron-binding in ETHE1, occupy similar positions to those observed across both the zinc 1 and zinc 2 binding sites in classical MBLs. The active site of hETHE1 is very similar to an ETHE1-like enzyme from Arabidopsis thaliana (60% sequence identity). A channel leading to the active site is sufficiently large to accommodate a GSSH substrate. Some of the observed hETHE1 clinical mutations cluster in the active site region. The structure will serve as a basis for detailed functional and mechanistic studies on ETHE1 and will be useful in the development of selective MBL inhibitors.

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Section: Discussionmentioning

confidence: 99%

Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy

Pettinati

Brem

McDonough

et al. 2015

Human Molecular Genetics

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“…Notably, the β-lactam antibiotic aztreonam does not contain such a carboxylate and is not an MBL substrate [108] , illustrating that is possible to obtain selectivity in binding to MBLs, even with related compounds. Various MBL inhibitors have been reported, principally in the academic literature, and some patents have been filed 109 , 110 . Perhaps the best-characterized MBL inhibitors are thiols, which displace the ‘hydrolytic’ water that bridges the two zinc ions that are found in clinically relevant MBLs [18] .…”

Section: Figurementioning

confidence: 99%

The Chemical Biology of Human Metallo-β-Lactamase Fold Proteins

Pettinati

Brem

Lee

et al. 2016

Trends in Biochemical Sciences

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The αββα metallo β-lactamase (MBL) fold (MBLf) was first observed in bacterial enzymes that catalyze the hydrolysis of almost all β-lactam antibiotics, but is now known to be widely distributed. The MBL core protein fold is present in human enzymes with diverse biological roles, including cell detoxification pathways and enabling resistance to clinically important anticancer medicines. Human (h)MBLf enzymes can bind metals, including zinc and iron ions, and catalyze a range of chemically interesting reactions, including both redox (e.g., ETHE1) and hydrolytic processes (e.g., Glyoxalase II, SNM1 nucleases, and CPSF73). With a view to promoting basic research on MBLf enzymes and their medicinal targeting, here we summarize current knowledge of the mechanisms and roles of these important molecules.

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“…In the case of MBLs, however, the design of clinically useful inhibitors of these enzymes has remained elusive. Nonetheless, a considerable number (of different classes) of compounds have been shown to serve as inhibitors of MBLs in vitro (see [11][12][13][14][15][16][17] for excellent reviews).…”

Section: Introductionmentioning

confidence: 99%