Identification of a Series of Tricyclic Natural Products as Potent Broad-Spectrum Inhibitors of Metallo-β-Lactamases
| Autor: | David G. Tew, Alfonso Rivera-Sagredo, Paloma Perez, Cheryl A. Janson, Nestor O. Concha, Martin Gilpin, Juan A. Hueso-Rodríguez, Michael Rees, John H. Bateson, Jesús Ángel de la Fuente, Helen F. Boyd, Niconovich Nancy, Stewart C. Pearson, Christy Cheever, David J. Payne, E. Diez, Stephen Rittenhouse |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular medicine.drug_class Klebsiella pneumoniae Antibiotics Bacillus Microbial Sensitivity Tests Chaetomium medicine.disease_cause beta-Lactamases Microbiology Bacillus cereus polycyclic compounds medicine Pharmacology (medical) Enzyme Inhibitors Antibacterial agent Pharmacology chemistry.chemical_classification Binding Sites biology Pseudomonas aeruginosa Drug Synergism Meropenem Chemistry Biosynthesis biochemical phenomena metabolism and nutrition bacterial infections and mycoses biology.organism_classification Kinetics Infectious Diseases Enzyme Biochemistry chemistry Enzyme inhibitor Fermentation Serratia marcescens biology.protein bacteria Thienamycins Bacteroides fragilis beta-Lactamase Inhibitors Heterocyclic Compounds 3-Ring |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 46:1880-1886 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Metallo-β-lactamases provide bacteria with an efficient and effective way of mediating resistance to β-lactam-based antibacterial agents. More significantly, they confer resistance to carbapenems. Therefore, if metallo-β-lactamases increase in prevalence, they could compromise the efficacy of this group of antibiotics to treat life-threatening hospital infections. Metallo-β-lactamases have now been identified in a wide spectrum of clinically important pathogens, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, and Acinetobacter sp. (21; H. Ito, K. Senda, T. Yagi, K. Shibayama, M. Ohta, N. Kato, and Y. Arakawa, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C-93, 1997). These enzymes also possess a proven capability to disseminate through bacterial populations, which is demonstrated by the spread of the IMP-1 metallo-β-lactamase in Japan (reviewed in reference 17). The spread of this enzyme is thought to be facilitated by its being encoded on an integron (1). More recently, clinical isolates producing metallo-β-lactamases have been identified in Europe (5, 12, 24). One approach to combating this potential clinical problem is the use of a specific metallo-β-lactamase inhibitor in combination with a β-lactam antibiotic. In this regard a range of different non-β-lactam based molecules have been identified as specific inhibitors of these enzymes. A series of mercaptoacetic acid thiol ester compounds were identified as mechanism-based, irreversible inhibitors of metallo-β-lactamases (18). Walter et al. (23) described a series of trifluoromethyl alcohol and ketone inhibitors that were competitive inhibitors of a range of metallo-β-lactamases, and a group of biphenyl tetrazole compounds have been shown to be specific inhibitors of the Bacteroides fragilis CfiA-type metallo-β-lactamase (22). None of these compounds exhibited significant synergy with β-lactam antibiotics, nor did they exhibit potent broad-spectrum inhibition of metallo-β-lactamases. However, a recently discovered series of mercaptocarboxylates have been shown to exhibit both broad-spectrum metallo-β-lactamase inhibitory activity and antibacterial synergy with meropenem (17). In our quest to identify novel inhibitors of metallo-β-lactamases, we screened natural product extracts against the Bacillus cereus II enzyme and identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-β-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract, and we now report on the purification, extraction, and characterization of this novel series of metallo-β-lactamase inhibitors derived from a natural product. |
| Databáze: | OpenAIRE |
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