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New 3D model of squalene epoxidase may explain mechanism of terbinafine resistance

May 23 2018

Trichophyton interdigitale and Trichophyton rubrum are the two predominant species of dermatophyte isolated from clinical samples in India, which are treated with allylamine antifungals. In a new study by  Dr Shivaprakash Rudramurthy and colleagues in Chandigarh (India), 16% (20/127) of Trichophyton isolates exhibited resistance to terbinafine, and the majority also showed resistance to naftifine.

Terbinafine inhibits squalene epoxidase (SQLE), leading to accumulation of squalene and depletion of ergosterol, thereby causing growth inhibition. SQLE gene sequences from terbinafine-resistant isolates were compared to those from terbinafine-sensitive isolates: 30% of resistant isolates had a T1189C transition in the gene sequence, corresponding with a Phe397Leu mutation in the protein.

Homology modelling of the wild type protein and the mutant protein revealed that the 3D structure of SQLE was destabilized by this radical amino acid substitution and that the mutation is located in the domain of the enzyme binding site, which may block the drug-enzyme binding leading to antifungal drug resistance.

Read the paper: Rudramurthy et al. (2018) Mutation in the Squalene Epoxidase Gene of Trichophyton interdigitale and Trichophyton rubrum Associated with Allylamine Resistance. Antimicrobial Agents and Chemotherapy 62(5):e02522-17

 

Homology modelling structure of SQLE, showing Phe (green) and Leu (red).