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Platform for bioprospecting the mechanism of action of antimicrobial molecules: proof of concept and validation

Abstract

There is a global crisis involving an increasing antibiotic resistance, especially against the ESKAPE pathogens (bacterial species which display resistance to currently used antibiotics: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa and Enterobacter sp). Therefore, it is imperative the development and identification of new antimicrobial agents.The absence of simple and practical functional assays to simultaneously determine the level of the antimicrobial activity and the molecular target of action of the putative compound is a significant bottleneck, once that the discovery of the mechanism of action is one of the longest steps in the preclinical phase (~ 5 years) for the discovery of new antibiotics. The company XYZ Molecular Target proposes in Phase 1 of the PIPE/FAPESP project to test the concept and validation of "ADP-MoA: Platform for Antibiotic Discovery by Mechanism of Action".This platform consists of a functional assay that uses a chemical-genetic strategy to identify antimicrobial molecules (by growth inhibition) and it simultaneously determines their mechanism of action (DNA damage, ribosome inhibition, or cell wall/membrane damage). ADP-MoA could decrease the time needed during the preclinical phase of discovering an antibiotic, in a relatively simple and low-cost way. The strategy uses a genetically modified strain of P. aeruginosa PA14, which contains a specific promoter (pSensor) fused to the lux reporter gene, which encodes the enzyme luciferase (lux). The pSensor::lux system is induced by natural or synthetic molecules that cause DNA damage, ribosome inhibition or cell wall damage, resulting in the formation of luminescence, thus allowing the observation of antimicrobial activity and identification of the molecule's mechanism of action, simultaneously.Compounds extracted from plants, filamentous fungi, bacteria or pure substances will be tested as proof of concept. To validate the large-scale application of the platform, will be established the standard conditions of analysis and miniaturization assays.This technology is a major advance in the ability to analyze sample collections of extracts, fractions and pure substances, which is of great interest to the pharmaceutical industry, research centers and companies dedicated to bioprospecting, this can help reduce the time required for the identification of new antibacterial compounds, through of High-Throughput Screening library of natural or synthetic molecules, at affordable cost.Brazil represents the seventh greatest pharmaceutical market of the world. However, more than 90% of all medicines and Active Pharmaceutical Supplies are imported. In fact, there is no commercially available antibiotic that have been locally developed and manufactured. This reality constitutes a national security problem in the area of health, evidencing a crisis as the current COVID-19 pandemic, in which the country, ran into difficulties in the internal production or importation of drugs for continuous use, becoming hostage to the market and the political, social and economic demands of other nations (AU)

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