Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds

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.

There is no market for new antibiotics: this allows an open approach to research and development

“…There exist biomedical research projects benefiting from the open sharing of data and expertise in this way in the areas of chemical probe discovery 80 , the physical sharing of drug libraries 81 , and in drug discovery 82 , 83 . Such pilots have shown how open projects can democratize discovery and development by allowing active participation by highly qualified people (individuals through to crowds) who may not otherwise have an avenue to contribute 84 . Interestingly, there are examples of valuable data freely shared from private sector programs only once the original program has been dropped (e.g., the sharing of Novartis and Achaogen data on the SPARK platform) 54 .…”

N‐Alkylated Aromatic Poly‐ and Oligoamides

“…The robustness of the methodologies developed for the submonomer synthesis of arylopeptoids make these types of N-alkylated aromatic oligomers highly suitable for educational purposes. [66] In the context of the Distributed Drug Discovery (D3) program, [67] a library of arylopeptoid dimers was screened to evaluate their activity on bacteria and yeasts. [66c] One dimer was found "partially active" on Cryptococcus neoformans.…”

Amino Alcohols as Potential Antibiotic and Antifungal Leads

“…Governments are starting to react through initiatives such as the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) initiative, but a significant number of pharmaceutical companies are no longer pursuing antibiotic development [ 10 , 11 , 12 ]. Despite a recent resurgence in antibiotic drug discovery, to date there has been limited progress in developing novel mode of action antibiotics [ 5 , 8 , 9 , 13 , 14 ].…”