Chimeric streptogramin-tyrocidine antibiotics that overcome streptogramin resistance.
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.
Mukhtar
Tariq A
TA
Antimicrobial Research Centre, Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street, West Hamilton, Ontario, L8N 3Z5, Canada.
Koteva
Kalinka P
KP
Wright
Gerard D
GD
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D008780:Methyltransferases / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013237:Stereoisomerism; D025361:Streptogramins / Q000737:chemistry* / Q000494:pharmacology; D014440:Tyrocidine / Q000737:chemistry* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D025361:Streptogramins; D014440:Tyrocidine; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase