Abstract
As hospital reports of strains of resistant bacteria are continuing to increase, a new approach is required for the identification of small molecules with antibacterial activity. Natural products that bind covalently to their biological target have been largely unexplored, although in the field of cancer chemotherapy, such molecules have been shown to counter resistance developed through efflux mechanisms. The azinomycins are potent antitumour agents that alkylate DNA and one of the natural products, compound 1, is a mono-alkylator that has been reported to retain potent antitumour activity. All four diastereomers of 1 were synthesized via a route involving late stage introduction of the epoxide stereocentre and separation of the resulting compounds. A non-alkylating analogue and a potential alkylator that cannot intercalate were also made. All four diastereomers are potent antibacterial agents in cell lines containing efflux-based resistance mechanisms. MIC values in the range of 0.25-1.0 μg/ml were observed. Comparison with the antitumour activity of the compounds suggests that the antibacterial activity stems from a similar mechanism of action involving DNA alkylation. As the ultimate molecular target of the azinomycins is unknown, bacterial strains may represent an interesting route for the discovery of the downstream mechanisms affected by DNA alkylation.
Keywords: P-glycoprotein efflux pump, cytotoxicity, anti-bacterial activity, Sharpless Asymmetric Epoxidation, column chromatography
Medicinal Chemistry
Title: Antitumour Antibiotics with Potent Activity Against Multidrug Resistant (MDR) Staphylococcus aureus: A New Approach to Targeting Resistant Bacteria
Volume: 1 Issue: 6
Author(s): M. A. Casely-Hayford, N. O. Kerr, E. Smith, S. Gibbons and M. Searcey
Affiliation:
Keywords: P-glycoprotein efflux pump, cytotoxicity, anti-bacterial activity, Sharpless Asymmetric Epoxidation, column chromatography
Abstract: As hospital reports of strains of resistant bacteria are continuing to increase, a new approach is required for the identification of small molecules with antibacterial activity. Natural products that bind covalently to their biological target have been largely unexplored, although in the field of cancer chemotherapy, such molecules have been shown to counter resistance developed through efflux mechanisms. The azinomycins are potent antitumour agents that alkylate DNA and one of the natural products, compound 1, is a mono-alkylator that has been reported to retain potent antitumour activity. All four diastereomers of 1 were synthesized via a route involving late stage introduction of the epoxide stereocentre and separation of the resulting compounds. A non-alkylating analogue and a potential alkylator that cannot intercalate were also made. All four diastereomers are potent antibacterial agents in cell lines containing efflux-based resistance mechanisms. MIC values in the range of 0.25-1.0 μg/ml were observed. Comparison with the antitumour activity of the compounds suggests that the antibacterial activity stems from a similar mechanism of action involving DNA alkylation. As the ultimate molecular target of the azinomycins is unknown, bacterial strains may represent an interesting route for the discovery of the downstream mechanisms affected by DNA alkylation.
Export Options
About this article
Cite this article as:
Casely-Hayford A. M., Kerr O. N., Smith E., Gibbons S. and Searcey M., Antitumour Antibiotics with Potent Activity Against Multidrug Resistant (MDR) Staphylococcus aureus: A New Approach to Targeting Resistant Bacteria, Medicinal Chemistry 2005; 1 (6) . https://dx.doi.org/10.2174/157340605774598126
DOI https://dx.doi.org/10.2174/157340605774598126 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Recent Patents on Proteasome Inhibitors of Natural Origin
Recent Patents on Anti-Cancer Drug Discovery Functionalized Nanocarriers for Enhanced Bioactive Delivery to Squamous Cell Carcinomas: Targeting Approaches and Related Biopharmaceutical Aspects
Current Pharmaceutical Design Cancer Chemoprevention by Dietary Phytochemicals: Promises and Pitfalls
Current Pharmaceutical Biotechnology Novel Biomarkers of microRNAs in Gastric Cancer: An Overview from Diagnosis to Treatment
MicroRNA Lactoferrin: A Biologically Active Molecule for Bone Regeneration
Current Medicinal Chemistry Selenium in the Therapy of Neurological Diseases. Where is it Going?
Current Neuropharmacology Evaluation of the Anticancer Activities of the Plant Alkaloids Sanguinarine and Chelerythrine in Human Breast Adenocarcinoma Cells
Anti-Cancer Agents in Medicinal Chemistry Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults
Current Medicinal Chemistry Peripheral Benzodiazepine Receptor (PBR) New Insight in Cell Proliferation and Cell Differentiation Review
Current Clinical Pharmacology Stimuli Responsive Nanoparticles for Controlled Anti-cancer Drug Release
Current Medicinal Chemistry Advances in Synergistic Combinations of Chinese Herbal Medicine for the Treatment of Cancer
Current Cancer Drug Targets Two Panels of Steroid Receptor Luciferase Reporter Cell Lines for Compound Profiling
Combinatorial Chemistry & High Throughput Screening A Perspective on Stem Cells as Biological Systems that Produce Differentiated Osteoblasts and Odontoblasts
Current Stem Cell Research & Therapy Celecoxib and Dimethylcelecoxib Block Oxidative Phosphorylation, Epithelial-Mesenchymal Transition and Invasiveness in Breast Cancer Stem Cells
Current Medicinal Chemistry Winning a Won Game: Caffeine Panacea for Obesity Syndemic
Current Neuropharmacology TRYCAT Pathways Link Peripheral Inflammation, Nicotine, Somatization and Depression in the Etiology and Course of Parkinson’s Disease
CNS & Neurological Disorders - Drug Targets Cancer Gene Therapy with Tissue Inhibitors of Metalloproteinases (TIMPs)
Current Gene Therapy Recent Developments on 1,2,4-Triazole Nucleus in Anticancer Compounds: A Review
Anti-Cancer Agents in Medicinal Chemistry Cancer and Aids: New Trends in Drug Design and Chemotherapy
Current Computer-Aided Drug Design Polo-Like Kinase 1 Pharmacological Inhibition as Monotherapy or in Combination: Comparative Effects of Polo-Like Kinase 1 Inhibition in Medulloblastoma Cells
Anti-Cancer Agents in Medicinal Chemistry