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Cellular Studies of an Aminoglycoside Potentiator Reveal a New Inhibitor of Aminoglycoside Resistance
Author(s) -
Guan Jinming,
Vong Kenward,
Wee Kathleen,
Fakhoury Johans,
Dullaghan Edie,
Auclair Karine
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800368
Subject(s) - aminoglycoside , potentiator , prodrug , antibiotics , chemistry , bacteria , pharmacology , microbiology and biotechnology , biology , biochemistry , genetics
Aminoglycosides are a group of broad‐spectrum antibiotics that have been used in the clinic for almost a century. The rapid spread of bacterial genes coding for aminoglycoside‐modifying enzymes has, however, dramatically decreased the utility of aminoglycosides. We have previously reported several aminoglycoside potentiators that work by inhibiting aminoglycoside N ‐6′‐acetyltransferase, one of the most common determinants of aminoglycoside resistance. Among these, prodrugs that combine the structure of an aminoglycoside with that of pantothenate into one molecule are especially promising. We report here a series of cellular studies to investigate the activity and mechanism of action of these prodrugs further. Our results reveal a new aminoglycoside resistance inhibitor, as well as the possibility that these prodrugs are transformed into more than one inhibitor in bacteria. We also report that the onset of the potentiators is rapid. Their low cell cytotoxicity, good stability, and potentiation of various aminoglycosides, against both Gram‐positive and Gram‐negative bacteria, make them interesting compounds for the development of new drugs.