Page 98 - Annual report 2021-22

Annual Report 2021-22 |

Bhupesh Taneja

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Bhupesh Taneja’s lab focuses on understanding mechanisms of antimicrobial resistance (AMR) in
bacteria and fungi. His group has carried out a comprehensive retrospective analysis of all
dermatophytosis (fungal skin infection) cases in India across 1038 research articles pertaining to
161245 patients from 1939-2021. They found a near-homogenous spread of dermatophytosis across
different decades between 1939 to 2010 but a sharp increase in the reported cases from 2011-2021
with nearly 50 % of evaluated cases reported in this decade alone, with a concomitant increase in
reported widespread failure to administered antifungal agents, especially terbinafine. In a cross-
sectional multi-centric observational study, comprising more than 300 cases of dermatophytosis, they
have found a significant number of reinfected (53%) or recalcitrant (38%) cases. Trichophyton
interdigitale was identified as the primary pathogenic agent responsible for ~94% of all cases followed
by T. rubrum (4% cases). Antifungal susceptibility test showed high MIC to terbinafine in naive cases
and to terbinafine and fluconazole in recalcitrant cases. His lab hence undertook whole genomic
sequencing and comparative genomics analysis of dermatophytes to identify key mutations and the
molecular basis of resistance associated with change in MICs to terbinafine.

18S rRNA sequence-based phylogenetic analysis indicates at least nine distinct genotypes for T.
mentagrophytes/ interdigitale species complex from across the world. T. interdigitale from India are
highly similar to each other and belong to genotype VIII and cluster separately from other genotypes
of other geographical locations of the world and recently termed as T. indotineae. Bhupesh's group is
working on genomics and transcriptomic signatures to antifungal treatment among responder and
non-responder T. indotineae strains to identify mechanisms of tolerance/resistance. He found that
SNPs associated with missense or upstream variations (both of which would likely affect expression of
final product) were associated with key pathways, viz., membrane transport, cell wall and membrane
biogenesis and secondary metabolites biosynthesis among the non-responder strains. This association
was confirmed by transcriptomics experiments using two different mutant strains grown with sub-
lethal concentration of terbinafine i.e. MIC20 that identified virulence-related pathways (LysM-
pathway and carbohydrate metabolism), MFS transporter (drug efflux), cell wall and membrane
structure (viz., chitinase, metal ion transport, siderophore biosynthesis) as the major gene ontology
categories which were affected in analyzed mutants.

To understand the molecular basis of terbinafine resistance, a mutation in Erg1 at position 397 (F397L)
was generated in silico and an all-atom molecular dynamic simulation in complex with FAD co-factor
was carried out (600 ns for WT and 350 ns for the mutant) followed by docking of terbinafine in the
mutant and WT proteins. Loss of pi-pi- stacking interactions with terbinafine were observed in the
mutant, highlighting the mechanistic role of these residues in drug response and providing a molecular
basis for drug resistance to terbinafine for the first time.

His group has also carried out phylogenomics analysis on another pathogenic fungi, i.e. mucor. An
increased number of mucormycosis cases (commonly described as black fungus) were reported from
different parts of the country, especially in the second wave of the COVID-19 pandemic. In
collaboration with St. Stephen's Hospital in North Delhi and GTB Hospital in East Delhi, 59 isolates