Chimeric streptogramin-tyrocidine antibiotics that overcome streptogramin resistance |
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Authors: | Mukhtar Tariq A Koteva Kalinka P Wright Gerard D |
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Affiliation: | Antimicrobial Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street, West Hamilton, Ontario, L8N 3Z5, Canada. |
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Abstract: | Streptogramin antibiotics are comprised of two distinct chemical components: the type A polyketides and the type B cyclic depsipeptides. Clinical resistance to the type B streptogramins can occur via enzymatic degradation catalyzed by the lyase Vgb or by target modification through the action of Erm ribosomal RNA methyltransferases. We have prepared through chemical and chemo-enzymatic approaches a series of chimeric antibiotics composed of elements of type B streptogramins and the membrane-active antibiotic tyrocidine that evade these resistance mechanisms. These new compounds show broad antibiotic activity against gram-positive bacteria including a number of important pathogens, and chimeras appear to function by a mechanism that is distinct from their parent antibiotics. These results allow for the development of a brand new class of antibiotics with the ability to evade type B streptogramin-resistance mechanisms. |
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