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Investigating Daptomycin-Membrane Interactions Using Native MS and Fast Photochemical Oxidation of Peptides in
Deseree J Reid1, Tapasyatanu Dash1, Zhihan Wang1
1Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Analytical Chemistry
|March 8, 2023
Summary
Daptomycin antibiotic activity is influenced by lipid membranes. New research uses mass spectrometry and FPOP to reveal how daptomycin interacts with bacterial membranes, showing stronger binding to rigid membranes.
Area of Science:
- Biochemistry
- Microbiology
- Biophysics
Background:
- Daptomycin is a vital cyclic lipopeptide antibiotic for treating Gram-positive bacterial infections.
- Understanding daptomycin's membrane interaction mechanisms is crucial but challenging due to the complexity of lipid bilayers.
- Membrane properties like fluidity and charge are known to modulate daptomycin's efficacy.
Purpose of the Study:
- To investigate the molecular interactions between daptomycin and lipid bilayers.
- To elucidate how different membrane characteristics affect daptomycin's integration and behavior.
- To explore the potential formation of membrane pores by daptomycin.
Main Methods:
- Utilized native mass spectrometry (MS) to analyze daptomycin's incorporation and oligomerization within lipid nanodiscs.
- Employed fast photochemical oxidation of peptides (FPOP) to probe daptomycin's accessibility and protection within various membrane environments.
- Conducted electrophysiology measurements to corroborate findings on daptomycin-induced membrane alterations.
Main Results:
- Native MS indicated random incorporation of daptomycin into bilayers without preference for specific oligomeric states.
- FPOP demonstrated significant protection of daptomycin across diverse lipid bilayer conditions.
- Combined MS and FPOP data revealed enhanced daptomycin-membrane interactions in more rigid bilayers and suggested pore formation in fluid membranes.
Conclusions:
- Native MS, FPOP, and electrophysiology are complementary techniques for studying antibiotic-membrane interactions.
- Daptomycin's interaction strength with lipid membranes is dependent on membrane rigidity.
- Evidence suggests daptomycin may form polydisperse pore complexes within bacterial membranes, impacting its activity.
