Our group expertise is in functional biology, chemical genetics, and high throughput screening for several phenotypic and experimental conditions. We screen the chemical libraries (small molecules, natural products, and FDA-approved drugs) to identify the interventions for aging. We combine our powerful approaches with multilayer functional analysis and identify the genes, proteins, and biological processes involved in the biology of aging and age-associated pathologies. Our group is also utilizing discovery-driven functional and chemical screening approaches to systematically identify the novel antifungal compounds and map the biological process landscapes of human fungal pathogenesis.
Aging population rapidly growing worldwide. Aging is the biggest risk factor for several human chronic ailments, including cancer, neurodegeneration, heart disease, diabetes, cognitive impairment and immune system decline (Figure 1). Aging is characterized by a progressive loss of physiological integrity, cellular functions and metabolic signaling. Such biological changes eventually lead to the prevalence of age-related pathologies, thereby compromise human health throughout life. Recent research in eukaryotic different model systems from single-celled yeast to nematode worms, fruit flies, mice and humans, has shown that aging mechanisms are conserved and delay aging is feasible by interventions including caloric restriction and drug administration. Our lab using budding yeast Saccharomyces cerevisiae as a model organism for study aging. The benefits of studying aging in yeast include a short generation time, a tractable life span, a genome-wide knockout library, its amenability to high-throughput functional assays and conservation of genes and pathways that uncover novel insights into human aging and interventions.
Figure 1 – Aging associated chronic diseases and fungal infections.
We are identifying antiaging compounds by screening the small molecules, natural products, and FDA-approved drugs repurposing. We have developed a robust and sensitive high throughput screening method for the identification of antiaging compounds. The antiaging compounds identified from the screen is further characterizing to understand their mechanism of action. We investigate the mechanism of antiaging compounds by target-based and non-target-based approaches (Figure 2). In target-based mechanism identification, we are directly testing the effect of antiaging compounds on the known hallmarks of aging, such as nutrient signaling, cellular stress, autophagy, mitochondrial integrity, and genome stability. In the non-target-based approach, we perform transcriptomics, proteomics, metabolomics, and phenotypic analysis and uncover the genes, proteins, and biological processes involved in aging interventions. Since several biological processes are incredibly dynamic, including their regulation, we comprehensively investigating antiaging action to understand the functional interactions at different biological layers. Antiaging compounds identified in yeast will be validated in human cells lines and different model systems like nematodes, flies and mice. In addition, we will perform the integrated analysis of multi-omics data to map the functional interactions of aging processes. This system biology-based approach would potentially enable us to identify the biological signature of antiaging compounds and novel aging biomarkers.
Figure 2 – Schematic representation of target and non-target- based approaches for identification of mechanisms of antiaging compounds.
HUMAN FUNGAL PATHOGENS
Fungal infections are widespread and rarely harmful for infected patients. However, invasive fungal infections are life-threatening, with mortality rates near 50% worldwide. The incidence of fungal infections is rising due to the increasing use of immunosuppressive drugs to treat organ transplant rejection, autoimmune disease, cancer, and growing immunocompromised individuals, particularly the aging population. Older people are associated with a progressive decline of physiological integrity and compromised immune systems that often accelerate invasive fungal infections. Candidiasis is the major fungal infection in the aged population largely caused by the pathogenic yeast species Candida. The primary causative agent of candidiasis is Candida albicans, even though the new Candida pathogens are emerging like C. auris, C. tropicalis, C. glabrata, C. parapsilosis, C. lusitaniae and C. krusei. Only three classes of antifungal drugs, polyenes (amphotericin B), azoles (fluconazole) and echinocandins (caspofungin), are available for the treatment of invasive fungal infections. The main reasons for the lack of effective antifungals include that fungal and human cells are functionally similar, leaving very few pathogen-specific drug targets. Moreover, fungal pathogens rapidly adapt to treatments and develop tolerance to antifungal drugs. In addition to the dearth of therapeutic options and drugs tolerance, the major antifungals are limited in use owing to their toxicity and severe side effects. Therefore, discovering potent antifungal drugs while maintaining low toxicity is an important medical need for invasive candidiasis therapy.
Our lab aim is to discover potent antifungal drugs for the treatment of invasive fungal infections. However, effective treatment is only possible if multiple virulence factors are inhibiting simultaneously. Therefore, the critical challenge in fungal interventions research is identifying inhibitors that target various virulence factors. Moreover, understanding all the biological players of pathogenicity is a crucial requirement to improve antifungal therapy further. Our lab is systematically screening the chemical libraries to identify the inhibitors for various virulence factors of different Candida species (Figure 3). We identify the inhibitors for various pathogenic factors like yeast cells, hyphal development and biofilms in favourable and stress conditions. We further elucidate the mechanism of action of inhibitors by functional analysis approaches and mapping the biological process of pathogenesis. We are unravelling the mechanism of action through concerted, cohesive efforts, including transcriptomics, proteomics, metabolomics and chemical genetics interaction analysis. We will provide the much-needed groundwork to identify the potent antifungal compounds and discover the specific virulence genes, proteins and biological pathways used to diagnose invasive fungal infections.
Figure 3 – Schematic representation of approaches to identify the human fungal pathogens virulence factors inhibitors and biological process of pathogenesis.