PolyChip â An Ultra High Throughput Microfluidic Functional Assay Strategy for Antimicrobial Drug Discovery.
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abstract
The continuous and ever increasing emergence of microbes with broad spectrum antibiotic resistance is a serious threat plaguing the world today. This threat is compounded by the relative lack of discovery of new antimicrobial drugs to keep in pace with the continuously and rapidly evolving microbes. Conventional antibiotic discovery approaches suffer from limitations arising due to time-consuming collection and screening approaches, exhaustion of culturable organisms as sources for antibiotics, and overdependence on targeted antibiotic discovery approaches. In this application, we propose a radical approach for addressing the limitations of conventional antibiotic discovery efforts by developing PolyChip, an integrated ultra-high throughput microfluidic platform that supports the identification and analysis of antimicrobial products generated by both culturable and unculturable microbes in direct functional bioassays with pathogens of high interest throughout the world, and especially in the Middle East. The aim of the proposal is to develop a microfluidic platform "PolyChip" that will continuously generate droplets each containing a predetermined number of microbes from environmental samples, allow merging of these with droplets containing fluorescently labeled pathogens of interest against which novel antimicrobials are desired, followed by on-chip co-cultivation and fluorescent analysis and sorting of droplets containing microbes that show antimicrobial activity for further analysis. In the second part of the proposal, as a proof of concept, we will use PolyChip to identify microbes with antimicrobial activity against two pathogens of high importance in Qatar and worldwide: Brucella melitensis and Acinetobacter baumannii. Last, we will isolate and characterize the antimicrobial compounds synthesized by microbes uncovered through our PolyChip screen. This may yield novel molecules with previously unrecognized mechanisms of microbial inhibition/attenuation, thus further advancing our knowledge of the biology and virulence of these key pathogens as an additional benefit. The results and the technology developed in this proposal will provide a direct functional assay at an unprecedented throughput with at least four orders of magnitudes improvement compared to conventional co-cultivation methods. It will also provide single-cell resolution, thus establishing a new paradigm in antimicrobial drug discovery that will be critical in future battles against drug resistant microbial infections.
