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Giving a Hand: Synthetic Peptides Boost the Antifungal Activity of Itraconazole against Cryptococcus neoformans
Tawanny K B Aguiar1, Ricardo M Feitosa1, Nilton A S Neto1
1Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza 60451-970, Brazil.
Abstract:
Cryptococcus neoformans is a multidrug-resistant pathogen responsible for infections in immunocompromised patients. Here, itraconazole (ITR), a commercial antifungal drug with low effectiveness against C. neoformans, was combined with different synthetic antimicrobial peptides (SAMPs), Mo-CBP3-PepII, RcAlb-PepII, RcAlb-PepIII, PepGAT, and PepKAA. The Mo-CBP3-PepII was designed based on the sequence of MoCBP3, purified from Moringa oleifera seeds. RcAlb-PepII and RcAlb-PepIII were designed using Rc-2S-Alb, purified from Ricinus communis seed cakes. The putative sequence of a chitinase from Arabidopsis thaliana was used to design PepGAT and PepKAA. All SAMPs have a positive liquid charge and a hydrophobic potential ranging from 41-65%. The mechanisms of action responsible for the combined effect were evaluated for the best combinations using fluorescence microscopy (FM). The synthetic peptides enhanced the activity of ITR by 10-fold against C. neoformans. Our results demonstrated that the combinations could induce pore formation in the membrane and the overaccumulation of ROS on C. neoformans cells. Our findings indicate that our peptides successfully potentialize the activity of ITR against C. neoformans. Therefore, synthetic peptides are potential molecules to assist antifungal agents in treating Cryptococcal infections.
Insights
Synthetic antimicrobial peptides (SAMPs) significantly boost itraconazole (ITR) effectiveness against Cryptococcus neoformans by 10-fold. These SAMPs enhance ITR
Area of Science:
- Mycology
- Antimicrobial drug development
- Biochemistry
Background:
- Cryptococcus neoformans is a multidrug-resistant fungal pathogen causing infections in immunocompromised individuals.
- Existing antifungal drugs like itraconazole (ITR) show limited efficacy against C. neoformans.
- There is a critical need for novel therapeutic strategies to combat C. neoformans infections.
Purpose of the Study:
- To investigate the synergistic potential of synthetic antimicrobial peptides (SAMPs) with itraconazole (ITR) against Cryptococcus neoformans.
- To evaluate the mechanisms of action underlying the enhanced antifungal activity of ITR-SAMP combinations.
- To explore novel therapeutic molecules for treating cryptococcal infections.
Main Methods:
- Design and synthesis of five SAMPs (Mo-CBP3-PepII, RcAlb-PepII, RcAlb-PepIII, PepGAT, PepKAA) based on various protein sequences.
- Combination studies of SAMPs with itraconazole against C. neoformans.
- Mechanism of action studies using fluorescence microscopy (FM) to assess membrane integrity and reactive oxygen species (ROS) production.
Main Results:
- SAMPs demonstrated a 10-fold enhancement of itraconazole's antifungal activity against C. neoformans.
- The most effective combinations induced pore formation in the fungal cell membrane.
- Combined treatment led to the overaccumulation of reactive oxygen species (ROS) within C. neoformans cells.
Conclusions:
- Synthetic antimicrobial peptides effectively potentiate the activity of itraconazole against C. neoformans.
- The synergistic effect is attributed to membrane disruption and ROS generation.
- SAMPs represent promising candidates to augment antifungal agents in treating cryptococcal infections.
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