MOLECULAR EVOLUTION OF BACTERIAL BETA-LACTAM RESISTANCE

Background: Two groups of penicillin-destroying enzymes, the class A a nd class C beta-lactamases, may have evolved from bacterial transpepti dases that transfer x-D-Ala-D-Ala peptides to the growing peptidoglyca n during cell wall synthesis. Both the transpeptidases and the beta-la ctamases are acylated by beta-lactam antibiotics such as penicillin, w hich mimic the peptide, but breakdown and removal of the antibiotic is much faster in the beta-lactamases, which lack the ability to process D-Ala-D-Ala peptides. Stereochemical factors driving this evolution i n specificity are examined. Results: We have compared the crystal stru ctures of two classes of beta-lactamases and a beta-lactam-sensitive D -alanyl-D-alanine carboxy-peptidase/transpeptidase (DD-peptidase). The class C beta-lactamase is more similar to the DD-peptidase than to an other beta-lactamase of class A. Conclusions: The two classes of beta- lactamases appear to have developed from an ancestral protein along se parate evolutionary paths. Structural differentiation of the beta-lact amases from the DD-peptidases appears to follow differences in substra te shapes. The structure of the class A beta-lactamase has been furthe r optimized to exclude D-alanyl peptides and process penicillin substr ates with near catalytic perfection.