Solanas, ConcepciónTorre, Beatriz G. de laFernández Reyes, MaríaSantiveri, Clara M.Jiménez, M. ÁngelesRivas, LuisJiménez, Ana I.Andreu Martínez, DavidCativiela, Carlos2019-02-212019-02-212010Solanas C, de la Torre BG, Fernández-Reyes M, Santiveri CM, Jiménez MA, Rivas L et al. Sequence inversion and phenylalanine surrogates at the beta-turn enhance the antibiotic activity of gramicidin S. J Med Chem. 2010;53(10):4119-29. DOI: 10.1021/jm100143f0022-2623http://hdl.handle.net/10230/36639A series of gramicidin S (GS) analogues have been synthesized where the Phe (i + 1) and Pro (i + 2) residues of the beta-turn have been swapped while the respective chiralities (D-, L-) at each position are preserved, and Phe is replaced by surrogates with aromatic side chains of diverse size, orientation, and flexibility. Although most analogues preserve the beta-sheet structure, as assessed by NMR, their antibiotic activities turn out to be highly dependent on the bulkiness and spatial arrangement of the aromatic side chain. Significant increases in microbicidal potency against both Gram-positive and Gram-negative pathogens are observed for several analogues, resulting in improved therapeutic profiles. Data indicate that seemingly minor replacements at the GS beta-turn can have significant impact on antibiotic activity, highlighting this region as a hot spot for modulating GS plasticity and activity.application/pdfengThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of medicinal chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm100143f.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1021/jm100143fGramidicin SCationic antimicrobial peptidesPhenylalanine analogsNMRβ-turnβ-sheet structureinfo:eu-repo/semantics/openAccess