Investigating Daptomycin–Membrane Interactions Using Native MS and Fast Photochemical Oxidation of Peptides in Nanodiscs

Daptomycin is a cyclic lipopeptide antibiotic that targets the lipid membrane of Gram-positive bacteria. Membrane fluidity and charge can affect daptomycin activity, but its mechanisms are poorly understood because it is challenging to study daptomycin interactions within lipid bilayers. Here, we co...

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Bibliographic Details
Published in:Analytical chemistry (Washington) 2023-03, Vol.95 (11), p.4984-4991
Main Authors: Reid, Deseree J., Dash, Tapasyatanu, Wang, Zhihan, Aspinwall, Craig A., Marty, Michael T.
Format: Article
Language:English
Subjects:
Analytical chemistry
Anti-Bacterial Agents - chemistry
Antibiotics
Bacteria
Chemistry
Complementarity
Daptomycin
Electrophysiology
Fluidity
Gram-positive bacteria
Lipid bilayers
Lipid Bilayers - chemistry
Lipid membranes
Lipids
Mass Spectrometry
Mass spectroscopy
Membrane conductance
Membrane fluidity
Membranes
Oxidation
Peptides
Photochemicals
Pore formation
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Summary:Daptomycin is a cyclic lipopeptide antibiotic that targets the lipid membrane of Gram-positive bacteria. Membrane fluidity and charge can affect daptomycin activity, but its mechanisms are poorly understood because it is challenging to study daptomycin interactions within lipid bilayers. Here, we combined native mass spectrometry (MS) and fast photochemical oxidation of peptides (FPOP) to study daptomycin–membrane interactions with different lipid bilayer nanodiscs. Native MS suggests that daptomycin incorporates randomly and does not prefer any specific oligomeric states when integrated into bilayers. FPOP reveals significant protection in most bilayer environments. Combining the native MS and FPOP results, we observed that stronger membrane interactions are formed with more rigid membranes, and pore formation may occur in more fluid membranes to expose daptomycin to FPOP oxidation. Electrophysiology measurements further supported the observation of polydisperse pore complexes from the MS data. Together, these results demonstrate the complementarity of native MS, FPOP, and membrane conductance experiments to shed light on how antibiotic peptides interact with and within lipid membranes.
ISSN:0003-2700
1520-6882
DOI:10.1021/acs.analchem.2c05222