Modulation of phospholipase A2 activity by aminoglycosides and daptomycin: a Fourier transform infrared spectroscopic study.
The antibiotics known as aminoglycosides are commonly used to treat severe infections caused by Gram-negative bacteria. Unfortunately, they often lead to acute renal failure after their accumulation in the lysosomes of renal cells, where an inhibition of the phospholipid catabolism is observed. The lipopeptidic antibiotic daptomycin has been shown to reduce the nephrotoxicity of aminoglycosides, but the exact mechanism of this protection is still unknown. In the present study, Fourier transform infrared spectroscopy (FTIR) has been used to monitor the hydrolysis of phosphatidylcholine by phospholipase A2 (PLA2) from Naja mocambique mocambique venom in the presence of various aminoglycosides and/or daptomycin. Gentamicin and amikacin inhibited the reaction in its early stage. Kanamycin A, tobramycin, and especially kanamycin B enhanced the initial enzyme activity by reducing the lag time. After the initiation period, the reaction proceeded at a much slower rate in the presence of gentamicin. On the other hand, daptomycin led to dramatic alterations of the hydrolysis profile: the initial latency period was eliminated, and the maximal extent of hydrolysis was reduced. When both daptomycin and any of the aminoglycosides were present, the latency period also disappeared, and the phospholipase activity was higher than with the lipopeptide alone. The most drastic change occurred with gentamicin, which was the most inhibitory aminoglycoside when used alone but worked synergistically with daptomycin to yield the most dramatic activation of PLA2.
Carrier
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D
Department of Biochemistry, Faculty of Medicine, University of Ottawa, Ontario, Canada. carrier@uottowa.ca
Bou Khalil
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M
Kealey
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A
D000617:Aminoglycosides / Q000494:pharmacology*; D000818:Animals; D017576:Daptomycin / Q000494:pharmacology*; D004357:Drug Synergism; D004546:Elapid Venoms / Q000201:enzymology*; D005839:Gentamicins / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D017550:Spectroscopy, Fourier Transform Infrared
D000617:Aminoglycosides; D004546:Elapid Venoms; D005839:Gentamicins; D008051:Lipid Bilayers; D008081:Liposomes; D010741:Phospholipases A; D054467:Phospholipases A2; D017576:Daptomycin