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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Ragonese, Heather Guogas, Laura M. Matson, Steven W. Redinbo, Matthew R. Lujan, Scott A. |
| Description | Author Affiliation: Lujan SA ( Department of Chemistry, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-3290, USA.); |
| Abstract | Conjugative transfer of plasmid DNA via close cell-cell junctions is the main route by which antibiotic resistance genes spread between bacterial strains. Relaxases are essential for conjugative transfer and act by cleaving DNA strands and forming covalent phosphotyrosine linkages. Based on data indicating that multityrosine relaxase enzymes can accommodate two phosphotyrosine intermediates within their divalent metal-containing active sites, we hypothesized that bisphosphonates would inhibit relaxase activity and conjugative DNA transfer. We identified bisphosphonates that are nanomolar inhibitors of the F plasmid conjugative relaxase in vitro. Furthermore, we used cell-based assays to demonstrate that these compounds are highly effective at preventing DNA transfer and at selectively killing cells harboring conjugative plasmids. Two potent inhibitors, clodronate and etidronate, are already clinically approved to treat bone loss. Thus, the inhibition of conjugative relaxases is a potentially novel antimicrobial approach, one that selectively targets bacteria capable of transferring antibiotic resistance and generating multidrug resistant strains. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 30 |
| Volume Number | 104 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2007-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA Nucleotidyltransferases Chemistry Metabolism Drug Resistance, Bacterial Drug Effects Enzyme Inhibitors Pharmacology Crystallography, X-Ray Antagonists & Inhibitors Genetics Diphosphonates Escherichia Coli Cytology Enzymology Microbial Viability Models, Molecular Protein Structure, Tertiary Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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