Abstract
Background: Candida auris is associated with invasive and severe candidemia, multi-drug resistance and high mortalities. Azoles and Flucytosine are commonly used antifungal drugs. Lanosterol alpha-demethylase (ERG11), Uracil phosphoribosyl transferase (FUR1) are two principal proteins involved in ergosterol biosynthesis and pyrimidine metabolism. However, crystal structures of these proteins from C. auris have not yet been established. We constructed structural model of ERG11 and FUR1 proteins for South-African Clade using homology modelling, molecular docking and molecular dynamics simulations. To investigate how point mutations affect drug interaction, we used the same methods on ERG11 mutants (Y132F, K143R) and FUR1 mutants (F211I). Methodology: Homology modelling was used to construct 3D structure of proteins. Reliability of models was analysed by using validation tools. The drug interaction in wild and mutant variants was studied using molecular docking, and binding energy was calculated. Finally, we investigated structural significance of point-mutation between two variants of FUR1 through MD Simulation. Result: Structural models of ERG11 and FUR1 were compared based on binding energy and hydrogen bonding. Few azole compounds showed no effect of mutation on interaction. Further, it was found that binding affinity for 5-fluorocytosine decreases in the mutant variant of FUR1. MD Simulation of wild variant FUR1-5FC complex showed stabilisation till 7ns while mutated complex was stable for 4.5ns. Conclusion: C. auris resistance to antifungal drugs poses a significant risk to public health. The study sheds light on how drug interactions are influenced by mutations and aids in the development of antifungal drugs.
Highlights
Antimicrobial resistance (AMR) has emerged as one of the leading public health crises of the 21st century that threatens the effective prevention and treatment of an expanding range of infections [1]
The effect of mutation as a common contributor to clinical resistance has not been investigated fully. In this context and in view of contributing to mutual interest of combating antimicrobial resistance (AMR), we report the effects of mutations on the interactions of antifungal drugs with their protein targets namely Lanosterol alphademethylase and Uracil phosphoribosyl transferase using molecular docking and molecular dynamics simulation studies
Previous research has shown that mutations in the South African clade's ERG11 Y132F and K143R and F211I in FUR1 increase drug resistance based on clinical data
Summary
Antimicrobial resistance (AMR) has emerged as one of the leading public health crises of the 21st century that threatens the effective prevention and treatment of an expanding range of infections [1]. While resistance in bacteria has been around for decades, a novel multidrug-resistant ascomycetes yeast pathogen belonging to the genus Candida was isolated from the external ear canal of a geriatric female inpatient in a Japanese hospital [3]. It was named as Candida auris as - auris in Latin means ‘ears’ [3]. We constructed structural model of ERG11 and FUR1 proteins for South-African Clade using homology modelling, molecular docking and molecular dynamics simulations. The drug interaction in wild and mutant variants was studied using molecular docking, and binding energy was calculated. The study sheds light on how drug interactions are influenced by mutations and aids in the development of antifungal drugs
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