A few gold compounds were recently found to show antimicrobial propertiesin vitro, holding great promise for the discovery of new drugs to overcome antibiotic resistance. Here, the inhibition of the bacterial virulence factor urease by four Au(i)-compounds, namely Au(PEt3)Cl, Au(PEt3)Br, Au(PEt3)I and [Au(PEt3)2]Cl, obtained from the antiarthritic Au(i)-drug Auranofin and earlier reported to act as antimicrobials, is investigated. The three monophosphino Au(i) complexes showed IC50values in the 30-100 nM range, while the diphosphino Au(i) complex, though being less active, still showed a IC50value of 7 μM. The structural basis for this inhibition was provided by solving the crystal structures of urease co-crystallized with Au(PEt3)I and [Au(PEt3)2]Cl: at least two Au(i) ions bind the enzyme in a flap domain involved in the catalysis, thus obliterating enzyme activity. Peculiar changes observed in the two structures reveal implications for the mechanism of soft metal binding and enzyme inactivation.

Medicinal Au(i) compounds targeting urease as prospective antimicrobial agents: unveiling the structural basis for enzyme inhibition

Cianci M.
Investigation
;
2021

Abstract

A few gold compounds were recently found to show antimicrobial propertiesin vitro, holding great promise for the discovery of new drugs to overcome antibiotic resistance. Here, the inhibition of the bacterial virulence factor urease by four Au(i)-compounds, namely Au(PEt3)Cl, Au(PEt3)Br, Au(PEt3)I and [Au(PEt3)2]Cl, obtained from the antiarthritic Au(i)-drug Auranofin and earlier reported to act as antimicrobials, is investigated. The three monophosphino Au(i) complexes showed IC50values in the 30-100 nM range, while the diphosphino Au(i) complex, though being less active, still showed a IC50value of 7 μM. The structural basis for this inhibition was provided by solving the crystal structures of urease co-crystallized with Au(PEt3)I and [Au(PEt3)2]Cl: at least two Au(i) ions bind the enzyme in a flap domain involved in the catalysis, thus obliterating enzyme activity. Peculiar changes observed in the two structures reveal implications for the mechanism of soft metal binding and enzyme inactivation.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11566/300077
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