期刊
ACS INFECTIOUS DISEASES
卷 3, 期 12, 页码 927-940出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.7b00128
关键词
antibiotic resistance; beta-lactamase; zinc; nutritional immunity; evolution
资金
- National Institutes of Health, National Institute of General Medical Sciences [GM111926, R01AI100560, R01AI063517, R01AI072219]
- National Institutes of Health, National Institute of Allergy and Infectious Disease [GM111926, R01AI100560, R01AI063517, R01AI072219]
- National Science Foundation [CHE-1509285]
- Robert A. Welch Foundation [F-1572]
- Miami University through the Robert H. and Nancy J. Blayney Professorship
- Cleveland Department of Veterans Affairs from the Biomedical Laboratory Research Development Service of the VA Office of Research and Development [1I01BX001974]
- Geriatric Research Education and Clinical Center VISN 10
- US Department of Energy [DE-AC03-76SF00098]
Use and misuse of antibiotics have driven the evolution of serine beta-lactamases to better recognize new generations of beta-lactam drugs, but the selective pressures driving evolution of metallo-beta-lactamases are less clear. Here, we present evidence that New Delhi metallo-/3-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Studies of NDM1, 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(11) concentrations relevant to infection sites. Each of the clinical variants is shown to be progressively more thermostable and to bind zinc(11) more tightly than NDM-I, but a selective enhancement of penam turnover at low zinc(11) concentrations indicates that most of the improvement derives from catalysis rather than stability. X-ray crystallography of NDM-4 and NDM-12, as well as bioinorganic spectroscopy of dizinc(1I), zinc(II)/cobalt(II), and dicobalt(11) metalloforms probe the mechanism of enhanced resistance and reveal perturbations of the dinuclear metal cluster that underlie improved catalysis. 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.
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