Executive Summary : | The mucormycosis (black fungus) is caused predominantly by Rhizopus arrhizus which also stands out to be the most common etiological agent of mucormycosis in India. While the exact disease burden is not known but prevalence of mucormycosis is much higher in India as compared to Western world due to the increased incidences of diabetes mellitus. Unfortunately, common and otherwise successful azoles- like fluconazole (FLC) and voriconazole (VCZ) are either ineffective or show limited activity against Mucorales. The polyene, Amphotericin B (AMB) remains the only front-line drug available for the treatment of Mucorales infections. Together, the unacceptable high mortality rate, limited options for therapy and the extreme morbidity underscore urgency in understanding the molecular mechanisms that govern pathogenesis and drug susceptibility. The progress thus far, however, provided only limited insights into the molecular basis of mucormycosis, leaving a vast gap in our understanding. Recent work from our as well as from other groups have shown that lipids which are the targets of azoles and polyenes do have a major impact in influencing drug susceptibility and virulence of other pathogenic fungi, however, this aspect has not been pursued in the cases of Mucorales and certainly needs to be explored. The proposed detailed understanding of lipid landscape and imbalances therein are expected to provide newer cues that may not only help in explaining limited success of azoles in treating Mucorales but will also help in understanding the molecular basis of antifungal resistance among this class of fungi. The proposed determination of the lipidomic landscape among Mucorales and between drug resistant and susceptible isolates will help in understanding how lipid impact the development of drug resistance in Mucorales? The planned study of transcriptomic and genomic landscape in response to drug exposure in Mucorales will first time provide an opportunity to disclose how and why Mucorales are intrinsically resistant to common azole antifungals and provide newer leads for improving therapeutic strategies. A group of leading experts in the field who bring in vast clinical (PGIMER), lipidomic, molecular mycology and computational (Amity, LU) experience have teamed up to address these challenges posed by Mucorales. Our preliminary data already point towards complete lack of Inositolphosphorylceramides in Mucorales which are otherwise common species among many pathogenic fungi. This data provides confidence that our team not only can perform the proposed work but is poised to discover molecular lipidomic cues influencing antifungal resistance to help design and improve treatment options to combat mucormycosis. |
Co-PI: | Dr. Amresh Prakash, Amity University, Noida, Uttar pradesh, Dr. Ashutosh Singh, University Of Lucknow, Uttar Pradesh-226007, Dr. Shivaprakash M Rudramurthy, Post Graduate Institute Of Medical Education And Research (PGIMER), Chandigarh-160012 |