High-Throughput Screening Platform for Novel Genetically-Encoded Secondary Metabolites to Address Antimicrobial Resistance

Antimicrobial resistance (AMR) is a severe emerging threat to the effective prevention and treatment of infections caused by bacteria, viruses, fungi, and parasites. Drug-resistant microbes are responsible for an estimated 700,000 deaths today, and future projections for the impact of unresolved AMR are as high as 10 million deaths per year by 2050.[1,2,3] Synthetic chemical collection screens for antibacterial discovery efforts have proven less than optimal for discovering new antimicrobials with a novel mechanism of action to address AMR.[4] Alternatively, recent advances in genome mining have confirmed the richness of biosynthetic gene clusters (BGCs) from microbial sources as a genomics-based discovery approach to screen for an untapped source of various chemicals and peptides with unique structures possessing potent biological activities.[5] To examine the products of some of these BGCs for novel antimicrobial activity against gram-negative pathogens, we have developed a high-throughput, miniaturized whole-cell screen that is lower volume and more sensitive than the traditional absorbance-based growth inhibition assay. Ginkgo Bioworks’ mission is to make biology easier to engineer. Utilizing a combination of Ginkgo’s strengths across sequencing, metagenomic mining, gene synthesis and expression, transcriptomics, mass spectrometry, and high-throughput screening, we present this screening platform to discover novel chemical classes of antibiotics to address AMR.





References:

[1] World Health Organization, Report to UN “No time to wait: securing the future from drug-resistant infections” 2019

[2] AMR Industry Alliance. 2020 progress report (AMR Industry Alliance, 2020)

[3] O’Neill, J. Tackling drug-resistant infections globally: final report and recommendations. The Review on Antimicrobial Resistance

[4] Miethke, M et al. “Towards the sustainable discovery and development of new antibiotics” Nature Reviews Chemistry (2021)

[5] Scherlach, K et al. “Mining and unearthing hidden biosynthetic potential” Nature Communications (2021)