title: Membrane Affinity of Platensimycin and Its Dialkylamine Analogs.
abstract: Membrane 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.
authors.affiliation: Department of Biology, University of Maryland, College Park, MD 20742, USA. ianrowe@umd.edu.|Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. ianrowe@umd.edu.
authors.forename: Ian
authors.initials: I
authors.lastname: Rowe
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. mguo@umd.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Biology, University of Maryland, College Park, MD 20742, USA. ayasmann@gmail.com.
authors.forename: Anthony
authors.initials: A
authors.lastname: Yasmann
authors.affiliation: Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA. cember@mail.med.upenn.edu.
authors.forename: Abigail
authors.initials: A
authors.lastname: Cember
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. hsintim@umd.edu.
authors.forename: Herman O
authors.initials: HO
authors.lastname: Sintim
authors.affiliation: Department of Biology, University of Maryland, College Park, MD 20742, USA. sukharev@umd.edu.|Maryland Biophysics Program, University of Maryland, College Park, MD 20742, USA. sukharev@umd.edu.
authors.forename: Sergei
authors.initials: S
authors.lastname: Sukharev
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology*; D062365:Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002463:Cell Membrane Permeability; D004926:Escherichia coli / Q000187:drug effects; D007473:Ion Channels / Q000378:metabolism
chemical_list: D062365:Aminobenzoates; D000813:Anilides; D000890:Anti-Infective Agents; D007473:Ion Channels; D000218:Adamantane; C510909:platensimycin
keywords: amphipathicity; drug insertion; hydrophobicity; lateral pressure; mechanosensitive channel; membrane permeability; monolayers