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Lipopeptide antibiotics disrupt interactions of undecaprenyl phosphate with UptA
Open accessPreprint — published as 10.1073/pnas.2408315121 · Paper page
Abstract
The peptidoglycan pathway represents one of the most successful antibacterial targets with the last critical step being the flipping of carrier lipid, undecaprenyl phosphate (C 55 -P), across the membrane to re-enter the pathway. This translocation of C 55 -P is facilitated by DedA and DUF368 domain-containing family membrane proteins via unknown mechanisms. Here we employ native mass spectrometry to investigate the interactions of UptA, a member of the DedA family of membrane protein from Bacillus subtilis , with C 55 -P, membrane phospholipids and cell wall-targeting antibiotics. Our results show that UptA, expressed and purified in E. coli , forms monomer-dimer equilibria, and binds to C 55 -P in a pH-dependent fashion. Specifically, we show that UptA interacts more favourably with C 55 -P over shorter-chain analogues and membrane phospholipids. Moreover, we demonstrate that lipopeptide antibiotics, amphomycin and aspartocin D, can directly inhibit UptA function by out-competing the substrate for the protein binding, in addition to their propensity to form complex with free C 55 -P. Overall, this study shows that UptA-mediated translocation of C 55 -P is potentially mediated by pH and anionic phospholipids and provides insights for future development of antibiotics targeting carrier lipid recycling.
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Metadata
- Authors
- Oluwole, A. O., Kalmankar, N., Guida, M., Bennett, J. L., Poce, G., Bolla, J. R., & Robinson, C. V.
- Affiliations
- University of Oxford (GB)
- Sapienza University of Rome (IT)
- Corresponding author
- Oluwole, Abraham O.
- Robinson, Carol V.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- openRxiv
- Published
- 2024-04-03
- Volume
- 121
- Issue
- 41
- Pages
- e2408315121-e2408315121
- ISSN
- 0027-8424 (ISSN-L)
- PMC
- PMC11474028
- OpenAlex
- W4403092653
- Cited by
- 13
- References
- 1
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 1
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (221795/Z/20/Z, 221795)
- UK Research and Innovation (MR/V028839/1)
- Royal Society (URF\R1\211567)
- University of Oxford
- Medical Research Council (MR/V028839/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Keywords
- undecaprenyl phosphate, lipopeptide antibiotics, Bacillus subtilis, protein-lipid interactions, pH-dependent binding, anionic phospholipids, membrane protein dimerization
- MeSH terms
- Anti-Bacterial Agents, Bacillus subtilis, Bacterial Proteins, Escherichia coli, Membrane Proteins, Polyisoprenyl Phosphates, Protein Binding, Lipopeptides
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