A Novel Polymyxin Derivative That Lacks the Fatty Acid Tail and Carries Only Three Positive Charges Has Strong Synergism with Agents Excluded by the Intact Outer Membrane
| Autor: | Juha Apajalahti, Osmo Siikanen, Timo Vaara, Niels Frimodt-Møller, Jian Li, John E. Fox, Hui He, Anima Poudyal, Roger L. Nation, Martti Vaara |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Cell Membrane Permeability medicine.drug_class Polymyxin Guinea Pigs Peptide Microbial Sensitivity Tests medicine.disease_cause Microbiology Structure-Activity Relationship 03 medical and health sciences Cricetulus Cricetinae Gram-Negative Bacteria medicine Animals Cationic Lipopeptides Pharmacology (medical) Lung Mechanisms of Action: Physiological Effects Escherichia coli Polymyxin B 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences biology 030306 microbiology Drug Synergism Fibroblasts biology.organism_classification Cyclic peptide Anti-Bacterial Agents Rats 3. Good health Infectious Diseases chemistry Colistin Enterobacter cloacae medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 54:3341-3346 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01439-09 |
| Popis: | Polymyxins are cationic lipopeptides (five cationic charges) and the last resort for the treatment of serious Gram-negative infections caused by multiresistant strains. NAB741 has a cyclic peptide portion identical to that of polymyxin B but carries in the linear peptide portion a threonyl-d-serinyl residue (no cationic charges) instead of the diaminobutyryl-threonyl-diaminobutyryl residue (two cationic charges). At the N terminus of the peptide, NAB741 carries an acetyl group instead of a mixture of methyl octanoyl and methyl heptanoyl residues. NAB741 sensitizedEscherichia coli,Klebsiella pneumoniae,Enterobacter cloacae, andAcinetobacter baumanniito antibiotics against which the intact outer membrane is an effective permeability barrier. When tested by using Etest strips on plates containing increasing concentrations of NAB741, the fractional inhibition concentration index (FICI) of the combination of NAB741 with rifampin ranged from ≤0.111 to 0.158 and that with clarithromycin from ≤0.094 to 0.292. When tested by the checkerboard method, the corresponding FICI values againstE. coliATCC 25922 were ≤0.141 to ≤0.155 with rifampin and 0.094 with clarithromycin. In addition, at 4 μg/ml, NAB741 decreased the MICs of azithromycin, mupirocin, fusidic acid, and vancomycin forE. colistrains andE. cloacaeby factors ranging from 8 to 200. A sister peptide, NAB752, carrying a threonyl-aminobutyryl residue as the linear peptide portion, was inactive. Furthermore, NAB741 sensitizedE. colito the bactericidal activity of fresh guinea pig serum. The renal clearance of NAB741 was approximately 400-fold, 16-fold, and 8-fold higher than those measured for colistin, NAB7061, and NAB739, respectively. |
| Databáze: | OpenAIRE |
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