Microbial heterogeneity-mediated treatment evasion and the potential for engineered live biotherapeutic products

Microbial populations exhibit both genetic and non-genetic heterogeneity. In the clinical context, this heterogeneity is of concern as it provides subsets of microbial populations with enhanced immune evasion abilities and antimicrobial resistance. Fungal pathogens are of special concern as fungal diseases and antifungal resistance are increasing worldwide and similarities between eukaryotic cells make it challenging to identify targets that are toxic to fungi without also harming the human host. Engineered live biotherapeutic products (eLBPs) could provide an alternative and complementary approach to manipulating and treating heterogeneous fungal populations due to their potential to provide localized delivery to the affected site, continuous long-term treatment, environmental sensing, and delivery of therapeutics specific to virulent or drug-resistant organisms. However, the development of eLBPs targeting fungi remains limited. This review assesses our current understanding of genetic and non-genetic microbial heterogeneity and how this impacts treatment strategies particularly for pathogenic fungi. We focus on Candida yeasts, specifically Candida albicans, as Candida species are the most common opportunistic fungal pathogens. We review the current scope and potential of eLBPs to address heterogeneous and rising fungal infections.