Membrane Affinity of Platensimycin and Its Dialkylamine Analogs

International Journal of Molecular Sciences

Ian Rowe³  Min Guo²  Anthony Yasmann³  Abigail Cember¹  Herman O. Sintim²  Sergei Sukharev³ 

[1] Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA; E-Mail:;Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA; E-Mails:;Department of Biology, University of Maryland, College Park, MD 20742, USA; E-Mails:

关键词: membrane permeability;    drug insertion;    hydrophobicity;    amphipathicity;    monolayers;    lateral pressure;    mechanosensitive channel;   

DOI  :  10.3390/ijms160817909

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.