Combined Antibacterial Effects of Goat Cathelicidins With Different Mechanisms of Action

Panteleev, Pavel V.; Bolosov, Ilia A.; Kalashnikov, Alexander A.; Kokryakov, Vladimir N.; Shamova, Olga V.; Emelianova, Anna A.; Balandin, Sergey V.; Ovchinnikova, Tatiana V.

Angol nyelvű Tudományos Szakcikk (Folyóiratcikk)
Megjelent: FRONTIERS IN MICROBIOLOGY 1664-302X 9 Paper: 2983 , 19 p. 2018
  • SJR Scopus - Microbiology (medical): Q1
Azonosítók
Being essential components of innate immune system, animal antimicrobial peptides (AMPs) also known as host-defense peptides came into sharp focus as possible alternatives to conventional antibiotics due to their high efficacy against a broad range of MDR pathogens and low rate of resistance development. Mammalian species can produce a set of co-localized AMPs with different structures and mechanisms of actions. Here we examined the combined antibacterial effects of cathelicidins, structurally diverse family of host-defense peptides found in vertebrate species. As a model we have used structurally distinct cathelicidins expressed in the leukocytes of goat Capra hircus. The recombinant analogs of natural peptides were obtained by heterologous expression in bacterial system and biological activities as well as the major mechanisms of antibacterial action of the peptides were investigated. As the result, the marked synergistic effect against wide panel of bacterial strains including extensively drug-resistant ones was observed for the pair of membranolytic alpha-helical amphipathic peptide ChMAP-28 and Pro-rich peptide mini-ChBac7.5N alpha targeting a bacterial ribosome. ChMAP-28 was shown to damage the outer bacterial membrane at sub-inhibitory concentrations that could facilitate Pro-rich peptide translocation into the cell. Finally, resistance changes under a long-term continuous selective pressure of each individual peptide and the synergistic combination of both peptides were tested against Escherichia coil strains. The combination was shown to keep a high activity after the 26-days selection experiment in contrast to mini-ChBac7.5N alpha used alone and the reference antibiotic polymyxin B. We identified the point mutation leading to amino acid substitution V102E in the membrane transport protein SbmA of the mini-ChBac7.5N alpha-resistant strain obtained by selection. The experiments revealed that the presence of sub-inhibitory concentrations of ChMAP-28 restored the activity of mini-ChBac7.5N alpha against this strain and clinical isolate with a weak sensitivity to mini-ChBac7.5N alpha. The obtained results suggest a potential medical application of synergistic combinations of natural cathelicidins, which allows using a lower therapeutic dose and minimizes the risk of resistance development.
Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSL
2019-11-19 01:54