Abstract
Correlating antifungal Azole drug resistance and mis-sense mutations of ERG11 has been paradoxical in pathogenic yeast Candida albicans. Amino acid substitutions (single or multiple) are frequent on ERG11, a membrane bound enzyme of Ergosterol biosynthesis pathway. Presence or absence of mutations can not sufficiently predict susceptibility. To analyze role of mis-sense mutations on Azole resistance energetically optimized, structurally validated homology model of wild C.albicans ERG11 using eukaryotic template was generated. A Composite Search Approach is proposed to identify vital residues for interaction at 3D active site. Structural analysis of catalytic groove, dynamics of substrate access channels and proximity of Heme prosthetic group characterized ERG11 active site. Several mis-sense mutations of ERG11 reported in C.albicans clinical isolates were selected through a stringent criterion and modeled. ERG11 mutants subsequently subjected to a four tier comparative biophysical analysis. This study indicates (i) critical interactions occur with residues at anterior part of 3D catalytic groove and substitution of these vital residues alters local geometry causing considerable change in catalytic pocket dimension. (ii) Substitutions of vital residues lead to confirmed resistance in clinical isolates that may be resultant to changed geometry of catalytic pocket. (iii)These substitutions also impart significant energetic changes on C.albicans ERG11 and (iv) include detectable dynamic fluctuations on the mutants. (v)Mis-sense mutations on the vital residues of the active site and at the vicinity of Heme prosthetic group are less frequent compared to rest of the enzyme. This large scale mutational study can aid to characterize the mutants in clinical isolates.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-660) contains supplementary material, which is available to authorized users.
Highlights
Candida albicans is an opportunistic fungal pathogen that causes various mucosal infections (Ge et al 2010) in general population and life-threatening systemic infections in immuno compromised patients (Feigal et al 1991, Richardson & Lass-Florl 2008)
The wild type ERG 11 of Candida albicans The wild type ERG 11 of Candida albicans was built using 4K0F.Protein data bank (PDB) (Lanosterol 14-alpha demethylase of Saccharomyces cerevisiae strain YJM789 with intact transmembrane domain bound to Itraconazole) resolved at 2.19 Å
It is apparent that significant geometrical changes in the 14a-Lanosterol demethylase of ergosterol synthesis pathway (ERG11) active site domain will take place if the amino acids responsible for key molecular interactions are substituted
Summary
Candida albicans is an opportunistic fungal pathogen that causes various mucosal infections (Ge et al 2010) in general population and life-threatening systemic infections in immuno compromised patients (Feigal et al 1991, Richardson & Lass-Florl 2008). The pathogenic yeast has been exposed to its conventional therapy of Azole drugs for a considerable period of time due to longer dosage regime in patients with deranged immunity This along with it’s over the counter use for topical applications have lead to Azole resistance, in C.albicans, a strategy to increase fitness against a constant challenge, a Because of the safety profile (Schweitzer et al 1996) and high therapeutic index, Azoles have been the drug of choice for many years as first-line therapy, antifungal prophylaxis and empirical or preemptive treatment (Morio et al 2010).
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