Broad-spectrum peptide inhibitors of aminoglycoside antibiotic resistance enzymes.
The action of aminoglycoside antibiotics is inhibited by chemical modification catalyzed by aminoglycoside inactivating enzymes, which bind these cationic saccharides with active site pockets that contain a preponderance of negatively charged residues. In this study, it was observed that several cationic antimicrobial peptides, representing different structural classes, could serve as inhibitors of such aminoglycoside resistance enzymes. The bovine antimicrobial peptide indolicidin and synthetic analogs appeared to be especially effective against a range of resistance enzymes, inhibiting enzymes belonging to both aminoglycoside phosphotransferase and aminoglycoside acetyltransferase classes, where the mode of action was dependent on the class of antibiotic resistance enzyme. These peptides represent the first example of broad-spectrum inhibitors of aminoglycoside resistance enzymes.
Boehr
David D
DD
Antimicrobial Research Centre, Department of Biochemistry, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
Draker
Kari-ann
KA
Koteva
Kalinka
K
Bains
Manjeet
M
Hancock
Robert E
RE
Wright
Gerard D
GD
D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000465:Algorithms; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology*; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D019868:Kanamycin Kinase / Q000037:antagonists & inhibitors; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; C073143:indolicidin; D000123:Acetyltransferases; C019681:aminoglycoside acetyltransferase; D019868:Kanamycin Kinase; D009713:Nucleotidyltransferases; C020565:gentamicin 2''-nucleotidyltransferase