Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-B-lactamase
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Title
Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-B-lactamaseDate
2015-09-15Publisher
ElsevierISSN
0003-9861Bibliographic citation
MELIÁ, Conchín, et al. Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-β-lactamase. Archives of biochemistry and biophysics, 2015, vol. 582, p. 116-126.Type
info:eu-repo/semantics/articlePublisher version
http://www.sciencedirect.com/science/article/pii/S0003986115000363Version
info:eu-repo/semantics/acceptedVersionSubject
Abstract
In this paper, hybrid QM/MM molecular dynamics (MD) simulations have been
performed to explore the mechanisms of hydrolysis of two antibiotics, Imipenen (IMI),
an antibiotic belonging to the subgroup of carbapenems, ... [+]
In this paper, hybrid QM/MM molecular dynamics (MD) simulations have been
performed to explore the mechanisms of hydrolysis of two antibiotics, Imipenen (IMI),
an antibiotic belonging to the subgroup of carbapenems, and the Cefotaxime (CEF), a
third-generation cephalosporin antibiotic, in the active site of a mono-nuclear β-
lactamase, CphA from Aeromonas hydrophila. According to our results, significant
different transition state structures are obtained for the hydrolysis of both antibiotics:
while the TS of the CEF is a ionic species with negative charge on nitrogen, the IMI TS
presents a tetrahedral-like character with negative charge on oxygen atom of the
carbonyl group of the lactam ring. Thus, dramatic conformational changes can take
place in the cavity of CphA to accommodate different substrates, which would be the
origin of its substrate promiscuity. This feature of the β-lactamase would be in turn,
associated to the different mechanisms that the protein employs to hydrolyze the
different antibiotics; i.e. the catalytic promiscuity. Since CphA shows only activity
against carbapenem antibiotic, this study will be used to shed some light into the origin
of the selectivity of the different MbL and, as a consequence, into the discovery of
specific and potent MβL inhibitors against a broad spectrum of bacterial pathogens. [-]
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Archives of biochemistry and biophysics, 2015, vol. 582Rights
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