Membrane Affinity of Platensimycin and Its Dialkylamine Analogs

dc.contributor.authorRowe, Ian
dc.contributor.authorGuo, Min
dc.contributor.authorYasmann, Anthony
dc.contributor.authorCember, Abigail
dc.contributor.authorSintim, Herman O.
dc.contributor.authorSukharev, Sergei
dc.date.accessioned2024-01-10T19:12:11Z
dc.date.available2024-01-10T19:12:11Z
dc.date.issued2015-08-04
dc.description.abstractMembrane permeability is a desired property in drug design, but there have been difficulties in quantifying the direct drug partitioning into native membranes. Platensimycin (PL) is a new promising antibiotic whose biosynthetic production is costly. Six dialkylamine analogs of PL were synthesized with identical pharmacophores but different side chains; five of them were found inactive. To address the possibility that their activity is limited by the permeation step, we calculated polarity, measured surface activity and the ability to insert into the phospholipid monolayers. The partitioning of PL and the analogs into the cytoplasmic membrane of E. coli was assessed by activation curve shifts of a re-engineered mechanosensitive channel, MscS, in patch-clamp experiments. Despite predicted differences in polarity, the affinities to lipid monolayers and native membranes were comparable for most of the analogs. For PL and the di-myrtenyl analog QD-11, both carrying bulky sidechains, the affinity for the native membrane was lower than for monolayers (half-membranes), signifying that intercalation must overcome the lateral pressure of the bilayer. We conclude that the biological activity among the studied PL analogs is unlikely to be limited by their membrane permeability. We also discuss the capacity of endogenous tension-activated channels to detect asymmetric partitioning of exogenous substances into the native bacterial membrane and the different contributions to the thermodynamic force which drives permeation.
dc.description.urihttps://doi.org/10.3390/ijms160817909
dc.identifierhttps://doi.org/10.13016/dspace/5wza-29kj
dc.identifier.citationRowe, I.; Guo, M.; Yasmann, A.; Cember, A.; Sintim, H.O.; Sukharev, S. Membrane Affinity of Platensimycin and Its Dialkylamine Analogs. Int. J. Mol. Sci. 2015, 16, 17909-17932.
dc.identifier.urihttp://hdl.handle.net/1903/31567
dc.language.isoen_US
dc.publisherMDPI
dc.relation.isAvailableAtCollege of Computer, Mathematical & Physical Sciencesen_us
dc.relation.isAvailableAtDigital Repository at the University of Marylanden_us
dc.relation.isAvailableAtBiologyen_us
dc.relation.isAvailableAtUniversity of Maryland (College Park, MD)en_us
dc.subjectmembrane permeability
dc.subjectdrug insertion
dc.subjecthydrophobicity
dc.subjectamphipathicity
dc.subjectmonolayers
dc.subjectlateral pressure
dc.subjectmechanosensitive channel
dc.titleMembrane Affinity of Platensimycin and Its Dialkylamine Analogs
dc.typeArticle
local.equitableAccessSubmissionNo

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