ChemInform Abstract: METAL‐ION CATALYZED HYDROLYSIS OF SOME β‐LACTAM ANTIBIOTICS

Gensmantel, Nigel P.; Proctor, Philip; Page, Michael I.

doi:10.1002/chin.198106093

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(2 citation statements)

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“…4B ), is reached within 30 ms. These results are consistent with the well-known fact that the anionic (at N4) open ring form of β-lactams has a very high p K a and is mostly protonated in solution in the absence of metal ions [12], [14], [30], [31]. What is shown here however is that hydrolyzed biapenem with the hydroxyethyl group rotated (as in Fig.…”

Section: Resultssupporting

confidence: 92%

“…6A ) acting as an apparent product inhibitor [29] . It is worth noting that this model is consistent with the long known fact that in solution the open-ring form of β-lactams is a strong base that at equilibrium is mostly protonated at N4 [12] , [14] , [30] , [31] . Our simulations only indicate that, from the kinetic point of view, the equilibrium corresponding to the bicyclic protonated derivative of carbapenems is reached through a path in which N4 is transiently ionized ( Fig.…”

Section: Discussionsupporting

confidence: 84%

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Biapenem Inactivation by B2 Metallo β-Lactamases: Energy Landscape of the Post-Hydrolysis Reactions

Gatti

2012

PLoS ONE

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BackgroundThe first line of defense by bacteria against β-lactam antibiotics is the expression of β-lactamases, which cleave the amide bond of the β-lactam ring. In the reaction of biapenem inactivation by B2 metallo β-lactamases (MβLs), after the β-lactam ring is opened, the carboxyl group generated by the hydrolytic process and the hydroxyethyl group (common to all carbapenems) rotate around the C5–C6 bond, assuming a new position that allows a proton transfer from the hydroxyethyl group to C2, and a nucleophilic attack on C3 by the oxygen atom of the same side-chain. This process leads to the formation of a bicyclic compound, as originally observed in the X-ray structure of the metallo β-lactamase CphA in complex with product.Methodology/Principal FindingsQM/MM and metadynamics simulations of the post-hydrolysis steps in solution and in the enzyme reveal that while the rotation of the hydroxyethyl group can occur in solution or in the enzyme active site, formation of the bicyclic compound occurs primarily in solution, after which the final product binds back to the enzyme. The calculations also suggest that the rotation and cyclization steps can occur at a rate comparable to that observed experimentally for the enzymatic inactivation of biapenem only if the hydrolysis reaction leaves the N4 nitrogen of the β-lactam ring unprotonated.Conclusions/SignificanceThe calculations support the existence of a common mechanism (in which ionized N4 is the leaving group) for carbapenems hydrolysis in all MβLs, and suggest a possible revision of mechanisms for B2 MβLs in which the cleavage of the β-lactam ring is associated with or immediately followed by protonation of N4. The study also indicates that the bicyclic derivative of biapenem has significant affinity for B2 MβLs, and that it may be possible to obtain clinically effective inhibitors of these enzymes by modification of this lead compound.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 84%

Biapenem Inactivation by B2 Metallo β-Lactamases: Energy Landscape of the Post-Hydrolysis Reactions

Gatti

2012

PLoS ONE

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ChemInform Abstract: METAL‐ION CATALYZED HYDROLYSIS OF SOME β‐LACTAM ANTIBIOTICS

Abstract: Kinetische Untersuchungen zeigen, daß Cu(II), Zn(II), Ni(II) und Co(II) die Hydrolyse einiger Penicillinund Cephalosporin‐Derivate um ein Vielfaches beschleunigen.

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Biapenem Inactivation by B2 Metallo β-Lactamases: Energy Landscape of the Post-Hydrolysis Reactions

Biapenem Inactivation by B2 Metallo β-Lactamases: Energy Landscape of the Post-Hydrolysis Reactions

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