Shikimate Pathway Inhibitors

Unmet Need
Antimicrobial and antibiotic resistance is rising to dangerously high levels throughout the world, posing a critical threat to human health and security. Each year in the United States, at least 2 million people are infected with antibiotic resistant bacteria, which results in at least 23,000 deaths. Thus, there is a great need to identify novel antimicrobial compounds with unique targets for treating infections and preventing the emergence and spread of resistance. High-throughput screens in microorganisms are ideal for drug discovery but can be cumbersome due to biosafety requirements and difficulty culturing certain pathogens for organism-specific assays, such as Mycobacterium tuberculosis or certain apicomplexan parasites. Consequently, a simple, modifiable, and streamlined approach is needed to identify potential candidate antimicrobials for all disease causing microorganisms that target a unique, but conserved pathogen-specific pathway.  
 
Technology Overview
Johns Hopkins researchers have developed a novel modifiable yeast synthetic biology platform that can be utilized to identify novel enzyme inhibitors of the well conserved, microorganism-specific, shikimate pathway, responsible for the production of aromatic amino acids. This system allows for multiplexed pathway-level screening, which increases the chances of identifying a novel therapeutic compound by up to seven-fold compared to individual target screens, and can identify compounds with broad spectrum activity. The yeast platform also allows for investigating the species-specificity of identified candidates using a series of “yeast avatars” that express enzymatic components of the shikimate pathway that are cloned from different microorganisms into Saccharomyces cerevisiae that are lacking parts or all of their homologous pathway. Finally, the system can be utilized to identify resistance mechanisms via drug selection and sequencing of the metabolic pathways encoded in the genetic elements that are subsequently isolated from survivor colonies.     
 
Stage of Development
The inventors have generated a yeast-based drug screening system that can be scalable for high-throughput approaches. Several yeast avatars have been generated thus far that include heterologous components of the shikimate pathway isolated from a number of pathogenic organisms that infect humans and plants. The next step will be developing additional avatars and screening candidate libraries to identify novel antimicrobials compounds for further research and development.   
 

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