Abstract
An increasing number of multidrug-resistant pathogens is a serious problem of modern medicine and new antibiotics are highly demanded. In this study, different n-alkyl acids (C2-C14) and aromatic acids (benzoic and trans-cinnamic) were conjugated to the N-terminus of KR12 amide. The effect of this modification on antimicrobial activity (ESKAPE bacteria and biofilm of Staphylococcus aureus) and cytotoxicity (human red blood cells and HaCaT cell line) was examined. The effect of lipophilic modifications on helicity was studied by CD spectroscopy, whereas peptide self-assembly was studied by surface tension measurements and NMR spectroscopy. As shown, conjugation of the KR12-NH2 peptide with C4-C14 fatty acid chains enhanced the antimicrobial activity with an optimum demonstrated by C8-KR12-NH2 (MIC 1–4 μg/mL against ESKAPE strains; MBEC of S. aureus 4–16 μg/mL). Correlation between antimicrobial activity and self-assembly behavior of C14-KR12-NH2 and C8-KR12-NH2 has shown that the former self-assembled into larger aggregated structures, which reduced its antimicrobial activity. In conclusion, N-terminal modification can enhance antimicrobial activity of KR12-NH2; however, at the same time, the cytotoxicity increases. It seems that the selectivity against pathogens over human cells can be achieved through conjugation of peptide N-terminus with appropriate n-alkyl fatty and aromatic acids.
Highlights
The occurrence of multidrug-resistant (MDR) bacterial strains faces many difficulties in the therapy of some infections due to prolonged treatment and frequent relapses
We report the synthesis of a series of lipopeptides derivatized with variable length fatty acids or aromatic acids covalently attached to the N-terminus of KR12-NH2, and their antimicrobial activity against planktonic cells of ESKAPE bacteria
For each of the synthesized lipopeptides, the activity against S. aureus as well as against bacteria of the ESKAPE group depended on the number of carbon atoms in the substituent
Summary
The occurrence of multidrug-resistant (MDR) bacterial strains faces many difficulties in the therapy of some infections due to prolonged treatment and frequent relapses. The therapy of infections caused by MRSA is even more challenging as these strains produce a number of mechanisms allowing them to invade into the organisms, including avoidance of opsonization by antibodies and complement system, disruption of chemotaxis and lysis of neutrophils. LL-37 is found in variety of cells, tissues and body fluids such as leukocytes, bone marrow, milk, salivary glands, skin, respiratory tract, epithelium cells and leukocytes within the digestive tract, urinary tract as well as squamous epithelium of the mouth and tongue [12,13,16,17] This compound exhibits a broad spectrum of antibacterial activity against both planktonic cells and biofilms of Gram-positive and Gram-negative bacteria, which promotes it as a candidate for a new antibiotic [18,19]. This peptide, a truncated form of LL-37, shares two common features of antimicrobial peptides: a positive net charge and an amphipathic structure, which determine their antimicrobial activity
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