Regulated Cell Death as a Therapeutic Target for Novel Antifungal Peptides and Biologics.
Michael R YeamanSabrina BüttnerKarin ThevissenPublished in: Oxidative medicine and cellular longevity (2018)
The rise of microbial pathogens refractory to conventional antibiotics represents one of the most urgent and global public health concerns for the 21st century. Emergence of Candida auris isolates and the persistence of invasive mold infections that resist existing treatment and cause severe illness has underscored the threat of drug-resistant fungal infections. To meet these growing challenges, mechanistically novel agents and strategies are needed that surpass the conventional fungistatic or fungicidal drug actions. Host defense peptides have long been misunderstood as indiscriminant membrane detergents. However, evidence gathered over the past decade clearly points to their sophisticated and selective mechanisms of action, including exploiting regulated cell death pathways of their target pathogens. Such peptides perturb transmembrane potential and mitochondrial energetics, inducing phosphatidylserine accessibility and metacaspase activation in fungi. These mechanisms are often multimodal, affording target pathogens fewer resistance options as compared to traditional small molecule drugs. Here, recent advances in the field are examined regarding regulated cell death subroutines as potential therapeutic targets for innovative anti-infective peptides against pathogenic fungi. Furthering knowledge of protective host defense peptide interactions with target pathogens is key to advancing and applying novel prophylactic and therapeutic countermeasures to fungal resistance and pathogenesis.
Keyphrases
- cell death
- drug resistant
- gram negative
- multidrug resistant
- public health
- small molecule
- antimicrobial resistance
- cell cycle arrest
- transcription factor
- acinetobacter baumannii
- amino acid
- candida albicans
- healthcare
- oxidative stress
- early onset
- human health
- emergency department
- pseudomonas aeruginosa
- climate change
- cell wall
- protein protein
- staphylococcus aureus
- smoking cessation
- risk assessment
- genetic diversity