Team:TJUSLS China

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We focus our project on hitting Achilles’ Heel of metallo-beta-lactamases (MBLs), a vital class of beta-lactamases without available clinical inhibitors, produced by drug-resistant pathogens. We want to obtain the broad-spectrum inhibitor of MBLs and lay the foundation for clinical trials in the future. Firstly we use synthetic biology methods to express a series of MBLs in E. coli, and then screen out effective inhibitor compounds via high-throughput screening with fluorescent probe (CDC-1) from FDA approved drug libraries and traditional Chinese medicine libraries. Also we assess their inhibitory ability in living bacterial cells by UV-vis spectroscopy. Finally, we obtained a series of effective inhibitors of MBLs, including an excellent broad-spectrum inhibitor, which can prevent living resistant bacteria from hydrolyzing beta-lactam antibiotics. We hope these inhibitors can be ideal candidates for therapeutics for diseases caused by drug-resistant pathogens.

Abstract
The Global Burden of MBLs

With the widespread use of antibiotics, the emergence of drug-resistant pathogens has become a great threat to human health. One of the most important resistance mechanisms is that bacteria can produce metallo- beta-lactamases (MBLs). The enzyme hydrolyzes almost all the beta-lactam antibiotics currently in use, making it a very difficult medical treatment problem.

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Our Solution

——To revive the conventional drug

Given the enormous cost and difficulty of developing new antibiotics, we are no longer targeting new antibiotics, choosing instead to find the broad-spectrum inhibitors that have a strong inhibitory effect on beta-lactamase from the approved drug libraries.

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Model

A virtual screening model has been built to discover the therapeutically effective compounds, in order to predict potential inhibitors. It narrows the scope of target inhibitors for the project via docking analysis. Our model allows for a more direct and rational drug discovery approach and has the advantage of low cost, massive coverage and effective screening.

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How did we achieve it?

Build Genetic Circuit

Determination of Enzyme Activity

Fluorescent HTS

UV-vision Detection

To obtain enzymes for test

To Build the system for HTS

To screen effective inhibitors from drug libraries

To evaluate therapeutic effects in E.coli

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Human Practices

From India--the hometown of NDM-type MBLs to Chinese medicine institution, communications, surveys and interviews connect our work with the world. Not only did human practices act as inseparable components of project improvement, but also we attempted to popularize the charming of synthetic biology.

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