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Many bacteria harbor genes clustered within their genome that encode the machinery to synthesize small molecules called natural products. These clustered genes are call biosynthetic gene clusters (BGCs) and many bacteria harbor 15-30 BGCs in their genome. BGCs have evolved to produce molecules with exquisite potency and selectivity, which has made them attractive and beneficial sources of drug leads. Our lab studies bacteria from marine ecosystems because these bacteria are less well studied compared to their terrestrial counterparts. As a result, the discovery rate of new scaffolds is much higher than traditional terrestrial bacteria.

We have developed mass spectrometry-based metabolomics workflows to assist with designing diversity libraries for high-throughput screening (HTS). See: 1-4 Selection of bacteria for production of small molecules is critical for drug discovery. Random selection of bacteria tends to lead to libraries with high levels of chemical redundancy, which can be a major problem for drug discovery efforts. Additionally, we have leveraged these tools to discover new natural product scaffolds.5-14

We have a major focus on discovery of antifungal and antibacterial natural products. We have developed infrastructure to purify natural products into 96-well plates for HTS. There are two primary reasons for purifying or partially purifying natural products prior to HTS: 1. Crude extracts are 80-90% media components, which masks the activity of natural products; and 2. Bacteria can produce multiple classes of natural products with different pharmacological activities. This work has led to the discovery of many new natural products.12, 15-17

  1. Hou, Y.; Braun, D. R.; Michel, C. R.; Klassen, J. L.; Adnani, N.; Wyche, T. P.; Bugni, T. S., Microbial Strain Prioritization Using Metabolomics Tools for the Discovery of Natural Products. Anal. Chem. 2012, 84 (10), 4277-4283.
  2. Chanana, S.; Thomas, C. S.; Braun, D. R.; Hou, Y.; Wyche, T. P.; Bugni, T. S., Natural Product Discovery Using Planes of Principal Component Analysis in R (PoPCAR). Metabolites 2017, 7 (3).
  3. Ellis, G. A.; Thomas, C. S.; Chanana, S.; Adnani, N.; Szachowicz, E.; Braun, D. R.; Harper, M. K.; Wyche, T. P.; Bugni, T. S., Brackish habitat dictates cultivable Actinobacterial diversity from marine sponges. PLoS One 2017, 12 (7), e0176968.
  4. Chanana, S.; Thomas, C. S.; Zhang, F.; Rajski, S. R.; Bugni, T. S., hcapca: Automated Hierarchical Clustering and Principal Component Analysis of Large Metabolomic Datasets in R. Metabolites 2020, 10 (7).
  5. Hou, Y.; Tianero, M. D.; Kwan, J. C.; Wyche, T. P.; Michel, C. R.; Ellis, G. A.; Vazquez-Rivera, E.; Braun, D. R.; Rose, W. E.; Schmidt, E. W.; Bugni, T. S., Structure and Biosynthesis of the Antibiotic Bottromycin D. Org Lett 2012, 14 (19), 5050-5053.
  6. Wyche, T. P.; Standiford, M.; Hou, Y.; Braun, D.; Johnson, D. A.; Johnson, J. A.; Bugni, T. S., Activation of the nuclear factor E2-related factor 2 pathway by novel natural products halomadurones A-D and a synthetic analogue. Mar Drugs 2013, 11 (12), 5089-99.
  7. Ellis, G. A.; Wyche, T. P.; Fry, C. G.; Braun, D. R.; Bugni, T. S., Solwaric acids A and B, antibacterial aromatic acids from a marine Solwaraspora sp. Mar Drugs 2014, 12 (2), 1013-22.
  8. Wyche, T. P.; Piotrowski, J. S.; Hou, Y.; Braun, D.; Deshpande, R.; McIlwain, S.; Ong, I. M.; Myers, C. L.; Guzei, I. A.; Westler, W. M.; Andes, D. R.; Bugni, T. S., Forazoline A: marine-derived polyketide with antifungal in vivo efficacy. Angew Chem Int Ed Engl 2014, 53 (43), 11583-6.
  9. Zhang, Y.; Adnani, N.; Braun, D. R.; Ellis, G. A.; Barns, K. J.; Parker-Nance, S.; Guzei, I. A.; Bugni, T. S., Micromonohalimanes A and B: Antibacterial Halimane-Type Diterpenoids from a Marine Micromonospora Species. J Nat Prod 2016, 79 (11), 2968-2972.
  10. Beemelmanns, C.; Ramadhar, T. R.; Kim, K. H.; Klassen, J. L.; Cao, S.; Wyche, T. P.; Hou, Y.; Poulsen, M.; Bugni, T. S.; Currie, C. R.; Clardy, J., Macrotermycins A-D, Glycosylated Macrolactams from a Termite-Associated Amycolatopsis sp. M39. Org Lett 2017, 19 (5), 1000-1003.
  11. Wyche, T. P.; Ruzzini, A. C.; Beemelmanns, C.; Kim, K. H.; Klassen, J. L.; Cao, S.; Poulsen, M.; Bugni, T. S.; Currie, C. R.; Clardy, J., Linear Peptides Are the Major Products of a Biosynthetic Pathway That Encodes for Cyclic Depsipeptides. Org Lett 2017, 19 (7), 1772-1775.
  12. Zhang, F.; Braun, D. R.; Ananiev, G. E.; Hoffmann, F. M.; Tsai, I. W.; Rajski, S. R.; Bugni, T. S., Biemamides A-E, Inhibitors of the TGF-beta Pathway That Block the Epithelial to Mesenchymal Transition. Org Lett 2018, 20 (18), 5529-5532.
  13. Zhang, F.; Braun, D. R.; Chanana, S.; Rajski, S. R.; Bugni, T. S., Phallusialides A-E, Pyrrole-Derived Alkaloids Discovered from a Marine-Derived Micromonospora sp. Bacterium Using MS-Based Metabolomics Approaches. J Nat Prod 2019, 82 (12), 3432-3439.
  14. Wu, Q.; Throckmorton, K.; Maity, M.; Chevrette, M. G.; Braun, D. R.; Rajski, S. R.; Currie, C. R.; Thomas, M. G.; Bugni, T. S., Bacillibactins E and F from a Marine Sponge-Associated Bacillus sp. J Nat Prod 2020.
  15. Zhang, F.; Barns, K.; Hoffmann, F. M.; Braun, D. R.; Andes, D. R.; Bugni, T. S., Thalassosamide, a Siderophore Discovered from the Marine-Derived Bacterium Thalassospira profundimaris. J Nat Prod 2017, 80 (9), 2551-2555.
  16. Zhang, F.; Zhao, M.; Braun, D. R.; Ericksen, S. S.; Piotrowski, J. S.; Nelson, J.; Peng, J.; Ananiev, G. E.; Chanana, S.; Barns, K.; Fossen, J.; Sanchez, H.; Chevrette, M. G.; Guzei, I. A.; Zhao, C.; Guo, L.; Tang, W.; Currie, C. R.; Rajski, S. R.; Audhya, A.; Andes, D. R.; Bugni, T. S., A marine microbiome antifungal targets urgent-threat drug-resistant fungi. Science 2020, 370 (6519), 974-978.
  17. Zhao, M.; Zhang, F.; Zarnowski, R.; Barns, K.; Jones, R.; Fossen, J.; Sanchez, H.; Rajski, S. R.; Audhya, A.; Bugni, T. S.; Andes, D. R., Turbinmicin inhibits Candida biofilm growth by disrupting fungal vesicle-mediated trafficking. J Clin Invest 2021, 131 (5).