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.

Discovery of new antibiotic candidates is driven by urgent global health needs and evolving resistance to current treatments. In pursuit of novel peptide-based antibiotics, more than 100 dipeptides containing fluorinated phenylalanine (F-Phe) residues were synthesized by undergraduate researchers at eight institutions and evaluated against Pseudomonas aeruginosa (P. aeruginosa) in a primary biofilm formation assay. Inclusion of multistep synthesis experiments in curricular laboratory courses at different institutions prompted the prioritization of robust and adaptable procedures that were effective at generating large compound sets for study. Several dipeptides were identified that inhibited biofilm formation at concentrations of 1 μg/mL or less. Further study of two of them, (S,S)-4-F-Phe-Ala and (S,S)-3,4-diF-Phe-Ala, revealed two distinct biological profiles. Inhibition of biofilm formation by (S,S)-4-F-Phe-Ala was directly associated with growth inhibition. In contrast, (S,S)-3,4-diF-Phe-Ala did not significantly inhibit bacterial growth at concentrations up to 100 μg/mL. Mammalian cell lines treated with either dipeptide at much higher concentrations remained viable, demonstrating selective toxicity for P. aeruginosa. Taken together, these data indicate that dipeptides comprising F-Phe are promising leads for the discovery of new antibiofilm therapeutics.

Despite thousands of cases yearly, African sleeping sickness (trypanosomiasis) receives limited research investment. Inhibition of the disease's late-stage CNS form remains challenging, with existing eflornithine-nifurtimox therapies exhibiting bone marrow toxicity. Rapid development of T. brucei resistance to existing treatments makes alternative mechanisms of inhibition