Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds.

Amelia A Fuller,William L Scott,Kristiana Tenorio,J Geno Samaritoni,Douglas Schirch,Sarah Burris-Hiday,Matthew A Cooper,Martin J O’Donnell,Johannes Zuegg,Amy B Dounay,Alysha G Elliott,Karl A Hansford,Jacob R Hitchens,Daniel G Rivera,Mark A T Blaskovich,Yanira Mendez

doi:10.1021/acschembio.0c00732

Abstract

New antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.

Highlights

New antibiotics are urgently needed to address increasing rates of multidrug resistant infections
multidrug resistant (MDR) infections are a consequence of overuse and misuse of existing antibiotics over the past several decades coupled with the ability of bacteria and fungi to rapidly develop varied resistance mechanisms.[2−4] There is a critical need to prioritize the identification and development of new therapeutic agents that can arrest and/or prevent microbial growth, including compounds that employ novel molecular mechanisms of action
Addressing the need for a reliable phenotypic screening resource, the Community for Open Antimicrobial Drug Discovery (CO-ADD) was launched in 2015 and has since tested over 300,000 compounds.[7−9] It affords free access to assess the antimicrobial activity of submitted compounds by testing their ability to inhibit growth of “ESKAPE” pathogens: Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA), and the yeasts Cryptococcus neoformans and Candida albicans

Summary

The significance of the inhibition values was determined by modified

Z-scores, calculated using the median and MAD of the samples (no controls) on the same plate. The antibiotics were provided in four concentrations, with 2 above and 2 below their MIC values, and plated into the first eight wells of column 23 of the Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia; orcid.org/00000003-2535-9071 Alysha G. Elliott − Community for Open Antimicrobial Drug Discovery, Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia; orcid.org/0000-. Yanira Mendez − Center for Natural Products Research, Faculty of Chemistry, University of Havana, 10400 La Habana, Cuba; orcid.org/0000-0003-2124-4912

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■ ACKNOWLEDGMENTS

■ REFERENCES