The increasing incidence of multi- and pan-resistant pathogens demands novel compounds to fight Grampositive
and especially Gram-negative bacteria. Among the currently investigated compound classes, antimicrobial peptides
(AMPs) inhibiting specific bacterial targets appear especially promising for systemic therapy of infections, although
unmodified linear peptides are typically rapidly degraded by serum proteases. Proline-rich AMPs have been heavily investigated
in recent years due to their low toxicity and proven in vivo efficacy. Here, we report novel unglycosylated drosocin
analogs with extended half-life in mouse serum and improved activity against Gram-negative pathogens Escherichia coli
and Klebsiella pneumoniae. Substituting proline (Pro) residues in positions 3, 5, 10, and 14 with trans-4-hydroxy-Lproline
(tHyp) improved the antibacterial activity, whereas substitution of Pro-16 reduced the activity. Drosocin analogs
with tHyp in positions 3 and 5 were also four to eight times more stable in mouse serum than the unmodified analog. The
new compounds were not toxic against human HeLa, HEK293, and HepG2 cell lines and showed no hemolytic activity
against human erythrocytes at peptide concentrations of at least 600 µg/mL.
Keywords: Antimicrobial peptide (AMP), Escherichia coli, hydroxyproline, serum stability, solid phase peptide synthesis.
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