Project 1: Functional roles of ncRNA afu-182 in azole response and pathobiology of Aspergillus fumigatus

TI: Sourabh Dhingra, PhD

Invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus is a major cause of morbidity and mortality in immune-compromised patients despite the availability of antifungal drugs. The global emergence of azole drug resistance is a major factor contributing to poor disease outcomes; however, azole drug-resistant A. fumigatus isolates contribute to only about 5% of infections. A major gap in knowledge is how azole sensitive isolates tolerate azole drugs and contribute to poor disease outcomes with mortality rates in excess of 50%. To this end, we have identified an uncharacterized long non-coding RNA (lncRNA) afu-182 that negatively correlates with azole drug response and is a driver of azole drug tolerance in the laboratory and clinical isolates. In this proposal, we will use genomics, genetics, biochemical approaches to define the mechanism of afu-182 mediated azole drug tolerance in A. fumigatus.

Project 2: Evaluating Anti-Parasitic Diazocyclobutenes

TI: Daniel Whitehead, PhD

Human African trypanosomiasis (HAT) is a neglected tropical disease that is endemic to sub-Saharan Africa, where millions are at risk for infection. The disease, which is caused by the eukaryotic pathogen Trypanosoma brucei, is typically fatal if untreated. Several therapeutic strategies are available, but outside of fexinidazole, these drugs are marred by relatively high toxicity, serious side-effects, and emerging resistance. Thus, there is a need for novel therapeutic strategies to treat this disease, and those caused by related organisms such as T. cruzi (American trypanosomiasis) and Leishmania spp. (leishmaniasis). Another protozoan target of our efforts, Trichomonas vaginalis, causes the most prevalent non-viral sexually-transmitted infection in the United States (ca. 3 million cases) with in excess of 120 million cases worldwide. Recently, we discovered a straightforward (one-step) route to synthesize a novel class of compounds, the diazacyclobutenes (DCBs), and we determined that some of them have potent anti-trypanosomal activity. The central goals of this proposal are to further explore the structureactivity relationship of these compounds as anti-trypanosomal agents, to uncover their mode of action in trypanosomes, and to explore their utility against another common parasite, Trichomonas vaginalis.