Gautam, I. | bioRxiv Science

bioRxiv2023

Structural Remodeling of Fungal Cell Wall Promotes Resistance to Echinocandins

The insufficient efficacy of existing antifungal drugs and the rise in resistance necessitate the development of new therapeutic agents with novel functional mechanisms1,2. Echinocandins are an important class of antifungals that inhibit {beta}-1,3-glucan biosynthesis to interfere with cell wall structure and function3,4. However, their efficacy is limited by the fungistatic activity against Aspergillus species and the trailing effect during clinical application. Here, we describe how echinocandins remodel the supramolecular assembly of carbohydrate polymers in the fungal cell wall in an unexpected manner, possibly resulting in a subsequent inhibition of the activity of these drugs. Solid-state nuclear magnetic resonance (ssNMR) analysis of intact cells from the human pathogenic fungus Aspergillus fumigatus showed that the loss of {beta}-1,3-glucan and the increase of chitin content led to a decrease in cell wall mobility and water-permeability, thus enhancing resistance to environmental stresses. Chitosan and -1,3-glucan were found to be important buffering molecules whose physical association with chitin maintained the wall integrity. These new findings revealed the difficult-to-understand structural principles governing fungal pathogens response to echinocandins and opened new avenues for designing novel antifungal agents with improved efficacy.

biophysics↗

bioRxiv2022

Genomic profiling of climate adaptation in Aedes aegypti along an altitudinal gradient in Nepal indicates non-gradual expansion of the disease vector

BackgroundDriven by globalization, urbanization and climate change, the distribution range of invasive vector species has expanded to previously colder ecoregions. To reduce health-threatening impacts on humans, insect vectors are extensively studied. Population genomics can reveal the genomic basis of adaptation and help to identify emerging trends of vector expansion. ResultsBy applying whole genome analyses and genotype-environment associations to populations of the main dengue vector Ae. aegypti, sampled along an altitudinal temperature gradient in Nepal (200- 1300m), we identify adaptive traits and describe the species genomic footprint of climate adaptation to colder ecoregions. We found two clusters of differentiation with significantly different allele frequencies in genes associated to climate adaptation between the highland population (1300m) and all other lowland populations ([≤] 800 m). We revealed non-synonymous mutations in 13 of the candidate genes associated to either altitude, precipitation or cold tolerance and identified an isolation-by-environment differentiation pattern. ConclusionOther than the expected gradual differentiation along the altitudinal gradient, our results reveal a distinct genomic differentiation of the highland population. This finding either indicates a differential invasion history to Nepal or local high-altitude adaptation explaining the populations phenotypic cold tolerance. In any case, this highland population can be assumed to carry pre-adapted alleles relevant for the species invasion into colder ecoregions worldwide that way expanding their climate niche.

genomics↗