A novel tool against multiresistant bacterial pathogens

• Verfasst von: Domhan, Cornelius [VerfasserIn]
• Verfasst von: Uhl, Philipp [VerfasserIn]
• Verfasst von: Meinhardt, Anna [VerfasserIn]
• Verfasst von: Zimmermann, Stefan [VerfasserIn]
• Verfasst von: Kleist, Christian [VerfasserIn]
• Verfasst von: Lindner, Thomas [VerfasserIn]
• Verfasst von: Leotta, Karin [VerfasserIn]
• Verfasst von: Mier, Walter [VerfasserIn]
• Verfasst von: Wink, Michael [VerfasserIn]
• Titel: A novel tool against multiresistant bacterial pathogens
• Titelzusatz: lipopeptide modification of the natural antimicrobial peptide ranalexin for enhanced antimicrobial activity and improved pharmacokinetics
• Verf.angabe: Cornelius Domhan, Philipp Uhl, Anna Meinhardt, Stefan Zimmermann, Christian Kleist, Thomas Lindner, Karin Leotta, Walter Mier, Michael Wink
• Jahr: 2018
• Umfang: 11 S.
• Fussnoten: Gesehen am 26.04.2019 ; Received 16 November 2017
• Titel Quelle: Enthalten in: International journal of antimicrobial agents
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1991
• Jahr Quelle: 2018
• Band/Heft Quelle: 52(2018), 1, Seite 52-62
• ISSN Quelle: 1872-7913
• DOI: doi:10.1016/j.ijantimicag.2018.03.023
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Antimicrobial peptide
• Sach-SW: Drug development
• Sach-SW: Lipopeptide
• Sach-SW: Multiresistant bacteria
• Sach-SW: Positron emission tomography
• Sach-SW: Ranalexin
• K10plus-PPN: 1663652473

Abstract

As evolutionarily optimised defence compounds, antimicrobial peptides (AMPs) represent a powerful tool against bacterial infections. Ranalexin, an AMP found in the skin of the American bullfrog (Rana catesbeiana), is primarily active against Gram-positive bacteria, with minimum inhibitory concentrations (MICs) of 8-16 mg/L, but shows weaker activity against Gram-negative bacteria (MICs > 64 mg/L). By substitution of six N-terminal amino acids by saturated fatty acids [decanoic acid (C10:0) to myristic acid (C14:0)], lipopeptide derivatives with enhanced antimicrobial activity were developed. The antimicrobial capacity of the peptides was tested against different bacterial strains, including multiresistant clinical isolates. C13C3lexin, the most potent derivative, showed MICs of 2-8 mg/L against Gram-positive bacteria and 2-16 mg/L against Gram-negative bacteria. In time-kill studies, it was clearly shown that ranalexin and the lipopeptide C13C3lexin function as concentration-dependent, fast-acting substances against different bacteria. Cell viability assays revealed that cytotoxicity towards human cells increases with the chain length of the attached fatty acid (IC50, 12.74-108.10 µg/mL). Furthermore, using positron emission tomography (PET) imaging, pharmacokinetic studies of 68Ga-labelled ranalexin and its derivatives were performed for the first time. Here it was demonstrated that ranalexin is rapidly cleared via the kidneys within 1 h post-injection. In contrast, the lipopeptide showed greatly extended circulation in the bloodstream and a shift from renal to hepatic accumulation characteristics. Therefore, the more favourable pharmacokinetics and enhanced antimicrobial activity clearly demonstrate the potential of the lipopeptide AMPs as novel ammunition against emerging multiresistant bacterial pathogens.