Restoration of susceptibility to amikacin by 8-hydroxyquinoline analogs complexed to zinc

• Published in: PloS one Vol. 14; no. 5; p. e0217602
• Main Authors: Magallon, Jesus, Chiem, Kevin, Tran, Tung, Ramirez, Maria S, Jimenez, Veronica, Tolmasky, Marcelo E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.05.2019; Public Library of Science (PLoS)
• Subjects: Acetylation; Acinetobacter baumannii - drug effects; Acinetobacter baumannii - pathogenicity; Acinetobacter Infections - drug therapy; Acinetobacter Infections - microbiology; Amikacin; Amikacin - adverse effects; Amikacin - pharmacology; Aminoglycosides; Aminoglycosides - pharmacology; Analysis; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics; Bacteria; Biology and Life Sciences; Clioquinol - pharmacology; Disease susceptibility; Drug Hypersensitivity - microbiology; Drug Resistance, Microbial - drug effects; Enzyme Inhibitors - pharmacology; Enzymes; HEK293 Cells; Humans; Ionophores; Medicine and Health Sciences; Pathogenic microorganisms; Physical Sciences; Toxicity; Zinc - chemistry; Zinc compounds
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0217602

Gram-negative pathogens resistant to amikacin and other aminoglycosides of clinical relevance usually harbor the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], an enzyme that catalyzes inactivation of the antibiotic by acetylation using acetyl-CoA as donor substrate. Inhibition of the acetylating reaction could be a way to induce phenotypic conversion to susceptibility in these bacteria. We have previously observed that Zn2+ acts as an inhibitor of the enzymatic acetylation of aminoglycosides by AAC(6')-Ib, and in complex with ionophores it effectively reduced the levels of resistance in cellulo. We compared the activity of 8-hydroxyquinoline, three halogenated derivatives, and 5-[N-Methyl-N-Propargylaminomethyl]-8-Hydroxyquinoline in complex with Zn2+ to inhibit growth of amikacin-resistant Acinetobacter baumannii in the presence of the antibiotic. Two of the compounds, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) and 5,7-diiodo-8-hydroxyquinoline, showed robust inhibition of growth of the two A. baumannii clinical isolates that produce AAC(6')-Ib. However, none of the combinations had any activity on another amikacin-resistant A. baumannii strain that possesses a different, still unknown mechanism of resistance. Time-kill assays showed that the combination of clioquinol or 5,7-diiodo-8-hydroxyquinoline with Zn2+ and amikacin was bactericidal. Addition of 8-hydroxyquinoline, clioquinol, or 5,7-diiodo-8-hydroxyquinoline, alone or in combination with Zn2+, and amikacin to HEK293 cells did not result in significant toxicity. These results indicate that ionophores in complex with Zn2+ could be developed into potent adjuvants to be used in combination with aminoglycosides to treat Gram-negative pathogens in which resistance is mediated by AAC(6')-Ib and most probably other related aminoglycoside modifying enzymes.