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.
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.