title: Fragment-based inhibitor discovery against β-lactamase.
abstract: The production of β-lactamase is one of the primary resistance mechanisms used by Gram-negative bacterial pathogens to counter β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems. There is an urgent need to develop novel β-lactamase inhibitors in response to ever evolving β-lactamases possessing an expanded spectrum of β-lactam hydrolyzing activity. Whereas traditional high-throughput screening has proven ineffective against serine β-lactamases, fragment-based approaches have been successfully employed to identify novel chemical matter, which in turn has revealed much about the specific molecular interactions possible in the active site of serine and metallo β-lactamases. In this review, we summarize recent progress in the field, particularly: the identification of novel inhibitor chemotypes through fragment-based screening; the use of fragment-protein structures to understand key features of binding hot spots and inform the design of improved leads; lessons learned and new prospects for β-lactamase inhibitor development using fragment-based approaches.
authors.affiliation: University of South Florida College of Medicine, Department of Molecular Medicine, 12901 Bruce B. Downs Blvd, MDC 3522, Tampa, FL 33612, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Nichols
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D057166:High-Throughput Screening Assays; D062105:Molecular Docking Simulation; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors