Molecular analysis of beta-lactamase structure and function.
The extensive and sometimes irresponsible use of beta-lactam antibiotics in clinical and agricultural settings has contributed to the emergence and widespread dissemination of antibiotic-resistant bacteria. Bacteria have evolved three strategies to escape the activity of beta-lactam antibiotics: 1) alteration of the target site (e.g. penicillin-binding protein (PBPs), 2) reduction of drug permeation across the bacterial membrane (e.g. efflux pumps) and 3) production of beta-lactamase enzymes. The beta-lactamase enzymes inactivate beta-lactam antibiotics by hydrolyzing the peptide bond of the characteristic four-membered beta-lactam ring rendering the antibiotic ineffective. The inactivation of the antibiotic provides resistance to the bacterium. Currently, there are over 300 beta-lactamase enzymes described for which numerous kinetic, structural, computational and mutagenesis studies have been performed. In this review, we discuss the recent work performed on the four different classes (A, B, C, and D) of beta-lactamases. These investigative advances further expand our knowledge about these complex enzymes, and hopefully, will provide us with additional tools to develop new inhibitors and antibiotics based on structural and rational designs.
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
Fahd K
FK
Majiduddin
Isabel C
IC
Materon
Timothy G
TG
Palzkill
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D006090:Gram-Negative Bacteria / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006094:Gram-Positive Bacteria / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D013329:Structure-Activity Relationship; D018440:beta-Lactam Resistance / Q000235:genetics; D001618:beta-Lactamases / Q000737:chemistry / Q000145:classification* / Q000378:metabolism*; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases