Sequence Inversion and Phenylalanine Surrogates at the β-Turn Enhance the Antibiotic Activity of Gramicidin S

• Published in: Journal of medicinal chemistry Vol. 53; no. 10; pp. 4119 - 4129
• Main Authors: Solanas, Concepción, de la Torre, Beatriz G, Fernández-Reyes, María, Santiveri, Clara M, Jiménez, M. Ángeles, Rivas, Luis, Jiménez, Ana I, Andreu, David, Cativiela, Carlos
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27-05-2010; American Chemical Society (ACS)
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Cationic antimicrobial peptides; Drug Resistance, Bacterial; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Gramicidin - analogs & derivatives; Gramicidin - chemical synthesis; Gramicidin - chemistry; Gramicidin - pharmacology; Gramidicin S; Hemolysis; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; NMR; Phenylalanine - chemistry; Phenylalanine analogs; Protein Structure, Secondary; Sheep; Structure-Activity Relationship; β-sheet structure; β-turn
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm100143f

A series of gramicidin S (GS) analogues have been synthesized where the Phe (i + 1) and Pro (i + 2) residues of the β-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 β-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 β-turn can have significant impact on antibiotic activity, highlighting this region as a hot spot for modulating GS plasticity and activity.