Biology subjects

Usmani, S. A.

Publications and source records attributed to Usmani, S. A..

2 recordsLinked to original sources

bioRxiv2026

Micafungin exposure drives multidrug resistance in Clavispora lusitaniae

Fungal infections are an escalating global health concern, with rare Candida species posing an urgent threat due to emerging multidrug resistance. Clavispora (Candida) lusitaniae is an uncommon pathogen in which multidrug resistance has been documented during antifungal therapy, yet the selective forces driving this phenotype remain unclear. Here, we show that exposure to the echinocandin micafungin (MCF) alone can select for multidrug resistance in C. lusitaniae. Through controlled evolution experiments we identified individual point mutations in genes encoding ergosterol biosynthesis enzymes (ERGs), sterol trafficking proteins (OSH2), and the echinocandin drug target (FKS1) that confer a significant fitness benefit to one or more classes of antifungals. We find that ERG3 loss-of-function is the primary and independent driver of pan-antifungal resistance to echinocandins, azoles and polyenes. The ERG3 mutants have <1% ergosterol, increased levels of non-toxic sterol intermediates, and increased chitin content, consistent with both cell membrane and cell wall remodeling that enables the fungal pathogen to evade all three drug classes. The convergence of sterol reprogramming and compensatory cell wall remodeling that occurs during adaptation to echinocandin monotherapy can evolve through a single point mutation and parallels our recent case study of acquired multidrug resistance. IMPORTANCEMultidrug resistance in Candida species severely limits treatment options and increases mortality, particularly in immunocompromised patients. Despite increasing reports of multidrug resistance, the molecular mechanisms driving multidrug resistance remain poorly understood. We find that in vitro MCF exposure alone can drive multidrug resistance in C. lusitaniae via acquisition of de novo point mutations in ERG3, an observation that parallels our recent patient case study. By identifying causative mutations and associated physiological changes, we provide mechanistic insight into the emergence of multidrug resistance and highlight the need for surveillance strategies that account for resistance evolution under echinocandin monotherapy.

microbiology↗

bioRxiv2024

Investigating the Structural Impact and Conformational Dynamics of a Sequence Variant (c.242G>A) in TMIE Gene Provoking Usher Syndrome

Usher syndrome (USH) is a retinal autosomal recessive genetic disorder, characterized by congenital severe-to-profound sensorineural hearing loss, retinitis pigmentosa (RP), and rarely vestibular dysfunction. A transmembrane inner ear gene TMIE causing autosomal recessive usher syndrome hearing loss, which may open up interesting perspectives into the function of this protein in inner ear. This disease is linked with mutations in TMIE gene. In this study delineates the pathogenic association, miss-fold aggregation, and conformational paradigm of a missense variant (c.242G>A) resulting into (p.Arg81His) in TMIE gene segregating usher syndrome through a molecular dynamics simulations approach. The transmembrane inner ear expressed protein assumes a critical role as its helices actively engage in binding with specific target DNA base pairs. The alteration observed in the mutant protein, characterized by an outward repositioning of the proximal helical portion, which is attributed to the absence of preceding beta-hairpins in the C-terminal region. This structural modification results in the loss of hydrogen bonds, exposure of hydrophobic residues to the solvent, and a consequential transformation of helices into loops, ultimately leading to functional impairment in the TMIE protein. These notable modifications in the stability and conformation of the mutant protein were verified through essential dynamics analysis, revealing that a point mutation induces distinct overall motions and correlations between proteins, ultimately resulting in usher syndrome. The current study provides insilico evidences of Usher syndrome hearing loss disease as protein folding disorder. The energy calculation also revealed that there is a difference of -251.211Kj/mol which also indicates that the SNP has significantly decreased the stability of protein consequently folding into Usher syndrome. This study contributes molecular insights into the structural correlation between the TMIE protein and usher syndrome. The docking analysis highlight various interaction between wild and mutant structure emphasizing key residues involved in hydrogen and hydrophobic interaction.

bioinformatics↗