Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents

点击翻译按钮获取中文摘要

Program Summary – Overview: The goal of this Center of Excellence for Translational Research (CETR) Program is to develop host-directed broad-spectrum anti-infective agents against NIAID priority pathogens by targeting the autophagy pathway. The most common approach for treating infectious diseases is to target pathogen-encoded proteins. However, pathogens can evolve resistance, and the spectrum of many clinically used anti-infective agents is restricted to taxonomically-related organisms. The use of host-directed anti-infective therapies offers several potential advantages to treating infectious diseases; including (1) the ability to target taxonomically-diverse pathogens; (2) decreased potential for promoting the emergence of drug-resistant organisms; and (3) the possibility of developing single compounds that target multiple pathogens, thereby decreasing the financial and regulatory barriers for developing anti-infective agents. Moreover, broad-spectrum host-directed therapeutics, once approved for clinical use against more common agents (in which clinical trials are feasible), can be deployed for emerging pathogens, new outbreaks, and pathogens engineered with ill intent. Proof-of-principle of this approach – namely, the development of effective host-directed broad-spectrum anti-infective therapeutics – could have a dramatic impact on how we treat and prevent infectious diseases. In recent years, extensive data have emerged (from our group of CETR investigators and others) indicating that degradative autophagy and autophagy-related (ATG) gene-dependent functions in immunity are crucial in host defense against taxonomically diverse pathogens. Furthermore, we and others showed that autophagy augmentation is safe and beneficial in animal models of infectious diseases. Therefore, the development of compounds that enhance autophagy and ATG gene- dependent immunity represents an attractive strategy for host-directed broad-spectrum anti-infective therapeutics. This new application has evolved from a currently funded, highly successful CETR Program entitled “Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents”. The goal of both the currently funded Program and this new proposal is to generate autophagy pathway-directed compounds that are active against a range of taxonomically-unrelated pathogens (selected based on priority status and medical need). To accomplish our goals, we will pursue a strategy that advances our current therapeutic leads and validates new targets to expand our discovery pipeline. We will accomplish our goals through five research projects entitled: RP1: Targeting Beclin 1 complexes for broad-spectrum anti-infective therapeutics. RP2: Targeting genes and pathways for autophagy-dependent inhibition of bacterial infection. RP3: Targeting Atg gene-dependent immunity for novel anti-infective therapeutics. RP4: Harnessing autophagy to treat tuberculosis. RP5: Chemical proteomic discovery of small-molecule probes for autophagy proteins. PHS 398/2590 (Rev. 06/09) Page