Skip to main content
SearchLoginLogin or Signup

Review 1: "A Synthetic Peptide Mimic Kills Candida Albicans and Synergistically Prevents Infection"

Reviewers provided positive feedback on the rationale, methods, and findings. The reviewers recognized the novelty of using these mimics as anti-fungal agents alone or in combination therapy.

Published onOct 26, 2023
Review 1: "A Synthetic Peptide Mimic Kills Candida Albicans and Synergistically Prevents Infection"
1 of 2
key-enterThis Pub is a Review of
A synthetic peptide mimic kills Candida albicans and synergistically prevents infection
A synthetic peptide mimic kills Candida albicans and synergistically prevents infection
Description

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually. Candida species are the most common cause of nosocomical, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat infections by Candida albicans. These synthetic polymers cause stress to the endoplasmic reticulum and affect protein glycosylation, a distinct mode of action compared to currently approved antifungal drugs. The most promising polymer composition caused damage to the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in a Galleria mellonella model of systemic candidiasis. Additionally, prolonged exposure of C. albicans to the synergistic combination of polymer and caspofungin did not lead to the evolution of resistant strains in vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

***************************************

Review:

The search for efficient anti-fungal therapies is more urgent than ever before. Invasive fungal infections caused by multi-resistant pathogens represent a significant and increasing burden to healthcare and society. Researchers investigating new classes of anti-fungal peptide mimics present one promising class that offers a potential solution to the multiple-drug-resistance problem due to their mode of action on the fungal cell wall with additional membrane-disrupting activities. 

The authors investigated the antifungal mode of action and therapeutic potential of four synthetic peptide mimics to combat infections by Candida albicans. The most promising polymer LH showed anti-Candida activities by targeting protein glycosylation and interfering with the fungal membrane. The leading candidate LH has been used as novel anti-fungal formulations as well as adjunctive anti-fungal therapy. 

Due to the evolutionary similarity of eukaryotic human and fungal cells, transcript profiling to investigate the mode of action of the antifungal polymers should also be done on normal human cells. To make sure minimal or no toxic effects to mammalian cell membranes, have the authors ever performed GO term and KEGG pathway enrichment analyses for mammalian/ human cell exposed to the polymers, with non-toxic poly-HEA as control?

The search for efficient anti-fungal therapies is more urgent than ever before. The biggest challenge is that the outcome of invasive candidiasis largely depends on the susceptibility of the pathogen to the antifungal treatment, which is NOT effective in immunocompromised patients. The authors also mentioned “an unfortunate consequence of these undeniably successful treatments for life-threatening diseases like cancer are severe infections caused by opportunistic pathogens”. Please address and discuss this important issue, e.g., for the high-risk groups, such as neutropenia, in patients with suppressed immune systems due to a variety of factors including cancer, HIV, and organ transplants, how will the polymers work and what is the toxicity to those people who are already very ill.

Different mouse models have been developed to recapitulate the different forms of candidiasis and murine models are considered to be the gold standard to study pathogenesis and analyze efficacy of antifungal treatment. The invertebrate Galleria mellonella model of systemic candidiasis is not an ideal model to mimic human situations, so interpreting data and transferring important insights to mammalian host should be done very carefully . There are many limitations and the authors should discuss the issue and consider mouse models for future study. 

Comments
0
comment
No comments here
Why not start the discussion?