![]() ![]() Our methods explicitly consider the propensity of a peptide to favor a binding-competent conformation, which we found to predict rank order of experimentally observed IC 50 values across seven designed NDM-1- inhibiting peptides. We present structure-guided computational methods for designing peptide macrocycles built from mixtures ofl- andd-amino acids that are able to bind to and inhibit targets of therapeutic interest. The rise of antibiotic resistance calls for new therapeutics targeting resistance factors such as the New Delhi metallo-β-lactamase 1 (NDM-1), a bacterial enzyme that degrades β-lactam antibiotics. Publication Date: Research Org.: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States) Sponsoring Org.: USDOE Office of Science (SC) OSTI Identifier: 1426739 Grant/Contract Number: AC02-05CH11231 AC03-76SF00098 Resource Type: Accepted Manuscript Journal Name: ACS Infectious Diseases Additional Journal Information: Journal Volume: 3 Journal Issue: 12 Journal ID: ISSN 2373-8227 Publisher: American Chemical Society (ACS) Country of Publication: United States Language: English Subject: 59 BASIC BIOLOGICAL SCIENCES 60 APPLIED LIFE SCIENCES antibiotic resistance evolution nutritional immunity zinc = , Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, and the CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology, Cleveland, OH (United States) Molecular Biology Consortium, Beamline 4.2.2, Advanced Light Source Miami University, Oxford, OH (United States).Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH (United States).Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, and the LaMontagne Center for Infectious Disease ![]() Lastly, these studies support the proposal that zinc(II) scarcity, rather than changes in antibiotic structure, is driving the evolution of new NDM variants in clinical settings. X-ray crystallography of NDM-4 and NDM-12, as well as bioinorganic spectroscopy of dizinc(II), zinc(II)/cobalt(II), and dicobalt(II) metalloforms probe the mechanism of enhanced resistance and reveal perturbations of the dinuclear metal cluster that underlie improved catalysis. Each of the clinical variants is shown to be progressively more thermostable and to bind zinc(II) more tightly than NDM-1, but a selective enhancement of penam turnover at low zinc(II) concentrations indicates that most of the improvement derives from catalysis rather than stability. Studies of NDM-1, NDM-4 (M154L), and NDM-12 (M154L, G222D) demonstrate that the point mutant M154L, contained in 50% of clinical NDM variants, selectively enhances resistance to the penam ampicillin at low zinc(II) concentrations relevant to infection sites. Here in this paper, we present evidence that New Delhi metallo-β-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Use and misuse of antibiotics have driven the evolution of serine β-lactamases to better recognize new generations of β-lactam drugs, but the selective pressures driving evolution of metallo-β-lactamases are less clear. ![]()
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