Abstract
IntroductionDue to the increase of antibiotic resistant bacterial strains, there is an urgent need for development of alternatives to antibiotics. Cathelicidins can be such an alternative to antibiotics having both a direct antimicrobial capacity as well as an immunomodulatory function. Previously, the full d-enantiomer of chicken cathelicidin-2 (d-CATH-2) has shown to prophylactically protect chickens against infection 7 days post hatch when administered in ovo three days before hatch. ObjectivesTo further evaluate d-CATH-2 in mammals as a candidate for an alternative to antibiotics.In this study, the prophylactic capacity of d-CATH-2 and two truncated derivatives, d-C(1–21) and d-C(4–21), was determined in mammalian cells. MethodsAntibacterial assays; immune cell differentiation and modulation; cytotoxicity, isothermal titration calorimetry; in vivo prophylactic capacity of peptides in an S. suis infection model. Resultsd-CATH-2 and its derivatives were shown to have a strong direct antibacterial capacity against four different S. suis serotype 2 strains (P1/7, S735, D282, and OV625) in bacterial medium and even stronger in cell culture medium. In addition, d-CATH-2 and its derivatives ameliorated the efficiency of mouse bone marrow-derived macrophages (BMDM) and skewed mouse bone marrow-derived dendritic cells (BMDC) towards cells with a more macrophage-like phenotype. The peptides directly bind lipoteichoic acid (LTA) and inhibit LTA-induced activation of macrophages. In addition, S. suis killed by the peptide was unable to further activate mouse macrophages, which indicates that S. suis was eliminated by the previously reported silent killing mechanism. Administration of d-C(1–21) at 24 h or 7 days before infection resulted in a small prophylactic protection with reduced disease severity and reduced mortality of the treated mice. Conclusiond-enantiomers of CATH-2 show promise as anti-infectives against pathogenic S. suis for application in mammals.
Highlights
Due to the increase of antibiotic resistant bacterial strains, there is an urgent need for development of alternatives to antibiotics
D-CATH-2 and its derivatives ameliorated the efficiency of mouse bone marrow-derived macrophages (BMDM) and skewed mouse bone marrow-derived dendritic cells (BMDC) towards cells with a more macrophage-like phenotype
Most of the subsequent assays were performed in cell culture medium RPMI + 10% fetal calf serum (FCS), which contains serum proteins and cationic ions that can influence the activity of cathelicidins [32,33]
Summary
Due to the increase of antibiotic resistant bacterial strains, there is an urgent need for development of alternatives to antibiotics. Cathelicidins are characterized by their highly conserved precursor cathelin-domain, but the active, mature peptides are highly variable in sequence and structure [4,6] They are strongly upregulated during infection [7,8] and despite their variable sequence, almost all cathelicidins show strong antimicrobial activity against many different bacteria [9], viruses [10,11], fungi [12,13], and parasites [14,15]. This antimicrobial activity is based on electrostatic membrane interactions, which makes resistance development less likely, as lipid targets can not mutate. Besides their direct multivalent antimicrobial activities, the immunomodulatory functions of these peptides makes them of special interest for potential clinical applications [5]
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