Sequence inversion and phenylalanine surrogates at the beta-turn enhance the antibiotic activity of gramicidin S.
A 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.
Solanas
Concepción
C
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, Zaragoza, Spain.
de la Torre
Beatriz G
BG
Fernández-Reyes
María
M
Santiveri
Clara M
CM
Jiménez
M Angeles
MA
Rivas
Luis
L
Jiménez
Ana I
AI
Andreu
David
D
Cativiela
Carlos
C
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006096:Gramicidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006461:Hemolysis; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D010649:Phenylalanine / Q000737:chemistry*; D017433:Protein Structure, Secondary; D012756:Sheep; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D006096:Gramicidin; D010649:Phenylalanine
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