Abstract:
The world is facing an antimicrobial crisis. Most antimicrobial drug development focuses on developing agents that kill pathogens. Unfortunately, new antimicrobials are rapidly hampered by the emergence of drug resistance. However, disease symptoms actually result from the combination of pathogen-derived effects and host mechanisms that kill pathogens but lead to collateral damage. These latter mechanisms represent a unique opportunity to develop resistance-proof treatments but are under-studied. Using an approach called “chemical cartography”, my laboratory combines liquid chromatography tandem mass spectrometry (LC-MS/MS), 3D modeling and data analytics with infection biology, to identify the spatial distribution of lipids and metabolites, and how they relate to infectious disease pathogenesis and microbiota dysbiosis. This knowledge is then used to guide rational drug development and improve our understanding of clinical treatment failure. In parallel, the costs of drug development are a barrier, especially for neglected and rare diseases. Using LC-MS/MS we have developed a method which rationally reduces the size of natural product extract high-throughput screening libraries by over 80% with minimal loss of bioactives across a variety of pathogen assays. Overall, our approach represents a new paradigm of using small molecule analysis to guide the development of novel treatment approaches for infectious diseases, with broad applicability.