Eukaryotic pathogens such as Leishmania are particularly challenging subjects of drug discovery efforts because their molecular machinery is structurally and mechanistically similar to our own, contributing to the risk of human drug toxicity. Our comparative genomic analyses indicate that the Leishmania protein synthesis machinery contains many unique and essential targets that differ substantially from their human counterparts. We will use a systems biological approach to build on preliminary findings and search for aminoacyl-tRNA- synthetase inhibitors with anti-leishmanial activity in a unique marine natural products library with proven efficacy against parasites. A high throughput screen will be implemented to generate preliminary leads, which will be validated in vitro and in vivo and used for testing in an established animal model for leishmaniasis. Such drugs could be used in a multidrug combination therapy, possibly with current anti-leishmanial agents, to exponentially reduce the probability of adaptive resistance. Because of our comparative systems biology approach, the proposed work will also be effective in identifying potential targets against other pathogenic kinetoplastids such as trypanosomes.
Infections caused by parasites like Leishmania are a leading cause of human morbidity and mortality worldwide, especially in developing countries. Leishmania are transmitted by a sand fly vector and cause a wide range of diseases, including visceral leishmaniasis (VL). It is estimated that VL causes over 50,000 deaths annually. Over 12 million people currently suffer from leishmaniasis in 98 countries, and more than 2 million are infected annually, making it a major global health problem and a neglected tropical disease. Leishmaniasis is increasingly seen in U.S. soldiers serving in Leishmania-endemic countries, such as Iraq and Afghanistan. Antimonials, amphotericin B, and miltefosine, the standard drugs used to treat leishmaniasis, are toxic. This leads to poor patient compliance and low-dose administration, ultimately contributing to the rise of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against different species of Leishmania, a challenge that will be directly addressed by the work proposed here.