Modulation of Phospholipase A₂ Activity by Aminoglycosides and Daptomycin:  A Fourier Transform Infrared Spectroscopic Study

Abstract

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.

Different modulation of phospholipase A2 activity by saturated and monounsaturated N-acylethanolamines

“…In the case of R ϭ 0.01, the cluster formation could be negligible, and the inhibiting action of NSEA could prevail. In fact, it is known that an increased cohesion of the lipid bilayer is detrimental to the lytic action of the enzyme (49). The hypothesis of different NPEA and NSEA interactions with DPPC headgroups is supported by Prodan results, which indicate an NAEs-induced reduced polarity in the probe microenvironment of these samples.…”

Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment

“…Daptomycin has shown no evidence of nephrotoxicity in humans or animals. In fact, data from rats suggest that it may provide protection against aminoglycoside nephrotoxicity (25)(26)(27). In clinical trials (17,28), daptomycin did not appear to pose risks of nephrotoxicity among patients with preserved renal function, and in fact, daptomycin has been used as a treatment option for patients with S. aureus infections who developed nephrotoxicity on vancomycin (29).…”

Liposome-encapsulated aminoglycosides in pre-clinical and clinical studies

“…Liposomes have also been studied as model membranes regarding the interaction of aminoglycosides with phospholipids in relation to aminoglycoside toxicity. [16][17][18][19] The…”