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Lipopeptide antibiotics disrupt interactions of undecaprenyl phosphate with UptA
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-10-03 , DOI: 10.1073/pnas.2408315121 Abraham O. Oluwole, Neha V. Kalmankar, Michela Guida, Jack L. Bennett, Giovanna Poce, Jani R. Bolla, Carol V. Robinson
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-10-03 , DOI: 10.1073/pnas.2408315121 Abraham O. Oluwole, Neha V. Kalmankar, Michela Guida, Jack L. Bennett, Giovanna Poce, Jani R. Bolla, Carol V. Robinson
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 reenter 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 Escherichia coli , forms monomer–dimer equilibria, and binds to C 55 -P in a pH-dependent fashion. Specifically, we show that UptA interacts more favorably with C 55 -P over shorter-chain analogs 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.
更新日期：2024-10-03
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