Antimicrobial effects of novel siderophores linked to β-lactam antibiotics
| Autor: | David R. Sherman, L Embuscado, T.E McKennon, Mike Langhorne, T Kline, E Naeemi, S. K. Tanaka, L. Goltry, S Cai, Lynn Barker, Ribhi Shawar, M Fromhold, A Bigelow, N Ihle, L. L. Brody, S.U Anderson, Mark J. Hickey, Lisa Nguyen, Paul Warrener, J Treiberg, P.R Witte, William R. Schwan |
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| Rok vydání: | 2000 |
| Předmět: |
Staphylococcus aureus
Siderophore Magnetic Resonance Spectroscopy Clinical Biochemistry Siderophores Pharmaceutical Science Microbial Sensitivity Tests beta-Lactams medicine.disease_cause Biochemistry Mass Spectrometry Drug Discovery Escherichia coli medicine Monobactam Molecular Biology Antibacterial agent biology Pseudomonas aeruginosa Chemistry Organic Chemistry Antimicrobial biology.organism_classification Enterobacteriaceae Anti-Bacterial Agents Molecular Medicine Bacterial outer membrane medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 8:73-93 |
| ISSN: | 0968-0896 |
| Popis: | As a strategy to increase the penetration of antibiotic drugs through the outer membrane of gram-negative pathogens, facilitated transport through siderophore receptors has been frequently exploited. Hydroxamic acids, catechols, or very close isosteres of catechols, which are mimics of naturally occurring siderophores, have been used successfully as covalently linked escorting moieties, but a much wider diversity of iron binding motifs exists. This observation, coupled to the relative lack of specificity of siderophore receptors, prompted us to initiate a program to identify novel, noncatechol siderophoric structures. We screened over 300 compounds for their ability to (1) support growth in low iron medium of a Pseudomonas aeruginosa siderophore biosynthesis deletion mutant, or (2) compete with a bactericidal siderophore-antibiotic conjugate for siderophore receptor access. From these assays we identified a set of small molecules that fulfilled one or both of these criteria. We then synthesized these compounds with functional groups suitable for attachment to both monobactam and cephalosporin core structures. Siderophore-beta-lactam conjugates then were tested against a panel of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus strains. Although several of the resultant chimeric compounds had antimicrobial activity approaching that of ceftazidime, and most compounds demonstrated very potent activity against their cellular targets, only a single compound was obtained that had enhanced, siderophore-mediated antibacterial activity. Results with tonB mutants frequently showed increased rather than decreased susceptibilities. suggesting that multiple factors influenced the intracellular concentration of the drugs. |
| Databáze: | OpenAIRE |
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