Electronic structures of cephalosporins and penicillins. 9. Departure of a leaving group in cephalosporins

Abstract

Molecular orbital calculations by the CNDO/2 method are used to study the potential energy surface for the stretching and rupturing of the CH2-OAc bond in a model cephalosporin structure, 7-amino-3-(acetoxymethyl)-3-cephem. The bond is easier to stretch and break when a nucleophilic group is in the vicinity of or attached to the beta-lactam carbonyl carbon (C8). The rate of acylation by a beta-lactam antibiotic at the receptor sites in bacterial cell-wall enzymes will be enhanced by a suitable leaving group at the 3' position. An orientational specificity is predicted for the direction of departure of the leaving group. Regardless of the direction the nucleophile approaches C8, the CH2-OAc bond is easiest to break when the acetate group departs from the alpha face of the molecule.

Recognition of the β-lactam carboxylate triggers acylation of Neisseria gonorrhoeae penicillin-binding protein 2

“…When comparing molecules of the asymmetric unit, a striking difference in the electron density for ceftriaxone is the presence of the C3 dioxo-triazine ring (R2 group) in molecule A. For ceftriaxone, this group is normally eliminated during acylation (24,25), but the electron density in molecule A indicates that the leaving group has remained attached even though acylation has completed (as indicated by the covalent bond between Ser-310 and ceftriaxone). This suggests that an intermediate stage has been trapped in molecule A of the asymmetric unit, whereas the reaction has proceeded to completion in molecule B.…”

Rapid point-of-care detection of the tuberculosis pathogen using a BlaC-specific fluorogenic probe

“…Extended spectrum class A β-lactamases are capable of hydrolysing all classes of β-lactam substrates, including cephalosporins. The mechanism of cephalosporin hydrolysis by β-lactamases yields hydrolysed β-lactam and, more importantly, may be concomitant with the loss of a 3′ leaving group 9–12 . Based on this mechanism, a number of fluorogenic and bioluminogenic probes were developed for the detection of β-lactamase activity in vitro , in living cells and even in whole animals 13–17 .…”

Fluorogenic Probes with Substitutions at the 2 and 7 Positions of Cephalosporin are Highly BlaC‐Specific for Rapid Mycobacterium tuberculosis Detection

“…Therefore, we started with an umbelliferone‐based, nonspecific β‐lactamase fluorogenic substrate (CDC‐1) and introduced a 2‐ethylthiomethyl substitution that produced two epimers ( 2R ‐CDC‐1, 2S ‐CDC‐1; Figure 1 B and Scheme S1 in the Supporting Information). Both CDC‐1 analogues were hydrolyzed by BlaC and TEM‐1 Bla, concurrently releasing the free umbelliferone (Figure 1 B) and generating a blue fluorescence signal 14. The catalytic constant ( k cat ) and the Michaelis constant ( K m ) for BlaC and TEM‐1 Bla are shown in Table S1 in the Supporting Information.…”