BLDB Presentation

Multidrug resistant (MDR) gram-negative pathogens, especially Enterobacteriaceae, are emerging worldwide. The MDR pattern is relatively common with resistance appearing to all major classes of anti-gram-negative agents (e.g. β-lactams, fluoroquinolones, and aminoglycosides), and in some cases, resistance to all available drugs. This is particularly worrisome in view of the current dearth of new compounds active against MDR gram-negatives in the pipeline.

β-Lactams, due to their safety, reliable killing properties and clinical efficacy, are among the most frequently prescribed antibiotics used to treat bacterial infections. However, their utility is being threatened by the worldwide proliferation of β-lactamases (BLs) with broad hydrolytic capabilities, especially in MDR gram-negative bacteria. These BLs are divided into 4 classes based on their sequence identities. Classes A, C and D contain active-site serine enzymes whose reaction pathways involve acylenzyme adducts while class B represents metallo-β-lactamases (MBLs) which do not form such intermediates (require zinc ion (s) for their function). Currently, BL-mediated resistance does not spare even the newest and most powerful β-lactams (i.e. carbapenems), whose activity is challenged by the MBLs (IMP, VIM, NDM, ...) as well as classes A and D serine-carbapenemases (KPC, IMI, GES, OXA-48, OXA-23, OXA-40, ...).

While a handful of β-lactamases were known in the early 1970’s, the number of β-lactamases has ever since been growing rapidly, especially with novel enzymes described, and the current dissemination of some enzymes in clinical isolates that undergo changes in their amino-acid sequence, yielding novel hydrolytic properties. The substrate specificities may be relatively narrow or broad including the extended-spectrum cephalosporins and the carbapenems. The class A enzymes (known primarily as penicillinases) tend to hydrolyze penicillins over cephalosporins as substrates although many variants may hydrolyze significantly broad-spectrum cephalosporins and carbapenems. The class B enzymes (metallo-β-lactamases) typically have an extremely broad-spectrum substrate specificity including all β-lactams except monobactams (aztreonam). The class C enzymes (cephalosporinases) tend to prefer cephalosporins as substrates whereas class D enzymes (oxacillinases) have an unusually high substrate preference for oxacillin and related penicillins. None of the marketed β-lactam molecules may resist to the hydrolysis by β-lactamases.

The aim of the Beta-Lactamase DataBase (BLDB) is to compile sequence information as well as biochemical and structural informations on all the currently known β-lactamases. BLDB offers in addition tools to analyze β-lactamases and provides important links to the related web resources (NCBI, PDB, etc.). This comprehensive web-based database, which is updated on a weekly basis, may provide at a glance useful insights in the structure-function relationships of β-lactamases, and thus allowing a better understanding of substrate specificities, determine key residues involved in substrate recognition and hydrolysis, and to forsee the impact of mutations in the hydrolysis profile.

Statistics

Enzymes:
Overall (8273); class A (1989); subclass B1 (617); subclass B2 (24); subclass B3 (311); class C (3844); class D (1291).

Structures:
Overall (1663); class A (626); subclass B1 (403); subclass B2 (16); subclass B3 (104); class C (246); class D (268).

Mutants:
Overall (167); class A (91); subclass B1 (35); subclass B2 (3); subclass B3 (6); class C (19); class D (13).

Kinetics:
Overall (47); class A (21); subclass B1 (3); subclass B2 (0); subclass B3 (4); class C (0); class D (19).