NovoBiotic Technology for Previously “Unculturable” Organisms 

Our founding scientists, Northeastern University professors Kim Lewis and Slava Epstein, developed in situ cultivation, enabling access to novel microorganisms from soil and marine environments (Kaeberlein et al., Science 2002). Cultivation occurs in a diffusion chamber placed in the natural environment from which the microorganisms were sampled. Growth factors from the environment diffuse into the chamber, enabling growth. Reinoculation from chamber to chamber produces “domesticated” variants capable of growing in the laboratory. We have cultured thousands of novel microorganisms using this approach. Based on 16S rDNA analysis, our collection is made of many novel species and genera only distantly related to known microorganisms. Multiple drug leads have been identified from producing organisms of this collection. 
Since the development of the original diffusion chamber, we have implemented new culturing technologies that improve access to uncultured microbes. These technologies include the “iChip”, a miniaturized version of the original chamber that allows isolation and cultivation of new microbes in a single step. A modified version of the diffusion chamber, the “trap”, selectively captures filamentous microbes, the most prolific producers of secondary metabolites. Using all our unique culturing technologies, we have built a strain collection of over 64,000 microbial isolates.

Objective research is of paramount importance to NovoBiotic Pharmaceuticals to ensure public trust and meet scientific, programmatic and ethical goals of our National Institutes Health (NIH) grant efforts. To view NovoBiotic Pharmaceuticals Financial Conflict of Interest Policy, click here.

Compounds

Teixobactin. Teixobactin is the first member of a new class of antibiotic that was discovered by NovoBiotic using our proprietary iChip technology (Ling et al., 2015). The compound is highly potent against a broad range of Gram-positive microbes, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Teixobactin is a bacterial cell wall synthesis inhibitor that acts by binding two different targets - lipid II (peptidoglycan precursor) and lipid III (teichoic acid precursor). It binds to the undecaprenyl-PP-sugar region of these precursors, which is not known to be subject to mutation. As a result, teixobactin is the first example of a target-specific compound essentially free of resistance. Teixobactin shows excellent activity in several models of infection, and is in preclinical development.

Clovibactin (Novo29) Clovibatin is another new antimicrobial compound discovered using NovoBiotic’s unique culturing platform. It is in preclinical development for treating a wide range of bacterial infections caused by Gram-positive pathogens including Staphylococcus aureus, Streptococcus pneumoniae, and Bacillus anthracis. Like teixobactin, Novo29 rapidly kills bacteria by inhibiting bacterial cell wall synthesis. No spontaneous resistance has been detected (<10-10 against S. aureus), and serial passaging studies in sublethal concentrations of clovibactin failed to generate resistance. However, clovibactin is smaller than teixobactin, and shows different binding characteristics to cell wall precursors. Clovibactin demonstrated excellent efficacy against MRSA in two mouse models of infection (septicemia and thigh infection), and low toxicity. All these results demonstrate promising potential for this exciting new compound to treat drug-resistant infections.

Lassomycin. Lassomycin is an inhibitor of the essential ClpP1P2C1 protease of mycobacteria, and forces the C1 ATPase to deplete ATP (Gavrish et al., 2014). The compound is highly selective against mycobacteria, including Mycobacterium tuberculosis, the causative agent of tuberculosis. Lassomycin is exceptionally good in killing both growing and dormant cells.

Publications

  1. Shukla R, Lavore F, Maity S, Derks MGN, Jones CR, Vermeulen BJA, Melcrová A, Morris MA, Becker LM, Wang X, Kumar R, Medeiros-Silva J, van Beekveld RAM, Bonvin AMJJ, Lorent JH, Lelli M, Nowick JS, MacGillavry HD, Peoples AJ, Spoering AL, Ling LL, Hughes DE, Roos WH, Breukink E, Lewis K, Weingarth M. Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature. 2022 Aug;608(7922):390-396. doi: 10.1038/s41586-022-05019-y. Epub 2022 Aug 3. PMID: 35922513; PMCID: PMC9365693.

  2. Krumberger M, Li X, Kreutzer AG, Peoples AJ, Nitti AG, Cunningham AM, Jones CR, Achorn C, Ling LL, Hughes DE, Nowick JS. Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29. J Org Chem. 2023 Feb 17;88(4):2214-2220. doi: 10.1021/acs.joc.2c02648. Epub 2023 Jan 19. PMID: 36655882; PMCID: PMC9942206.

  3. Wirtz DA, Ludwig KC, Arts M, Marx CE, Krannich S, Barac P, Kehraus S, Josten M, Henrichfreise B, Müller A, König GM, Peoples AJ, Nitti A, Spoering AL, Ling LL, Lewis K, Crüsemann M, Schneider T. Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin. Angew Chem Int Ed Engl. 2021 Jun 7;60(24):13579-13586. doi: 10.1002/anie.202102224. Epub 2021 May 7. PubMed PMID: 33768646; PubMed Central PMCID: PMC8252469. [PDF]

  4. Espinoza JL, Dupont CL, O'Rourke A, Beyhan S, Morales P, Spoering AL, Meyer KJ, Chan AP, Choi Y, Nierman WC, Lewis K, Nelson KE (2021) Predicting antimicrobial mechanism-of-action from transcriptomes: A generalizable explainable artificial intelligence approach. PLoS Comput Biol. 17(3). PMID: 33780444 [PDF]

  5. Wirtz DA, Ludwig KC, Arts M, Marx CE, Krannich S, Barac P, Kehraus S, Josten M, Henrichfreise B, Müller A, König GM, Peoples AJ, Nitti A, Spoering AL, Ling LL, Lewis K, Crüsemann M, Schneider T (2021) Biosynthesis and Mechanism of Action of the Cell Wall Targeting Antibiotic Hypeptin. Angew Chem Int Ed Engl. PMID: 33768646 [PDF]

  6. Quigley J, Peoples A, Sarybaeva A, Hughes D, Ghiglieri M, Achorn C, Desrosiers A, Felix C, Liang L, Malveira S, Millett W, Nitti A, Tran B, Zullo A, Anklin C, Spoering A, Ling LL, Lewis K (2020) Novel Antimicrobials from Uncultured Bacteria Acting against Mycobacterium tuberculosis. mBio. Aug 4 11(4):e01516-20. PMID: 32753498 [PDF]

  7. Lawrence WS, Peel JE, Sivasubramani SK, Baze WB, Whorton EB, Beasley DWC, Comer JE, Hughes DE, Ling LL, Peterson JW (2020) Teixobactin Provides Protection against Inhalation Anthrax in the Rabbit Model. Pathogens. Sep 22 9(9):773. PMID: 32971758 [PDF]

  8. O'Rourke A, Beyhan S, Choi Y, Morales P, Chan AP, Espinoza JL, Dupont CL, Meyer KJ, Spoering A, Lewis K, Nierman WC, Nelson KE (2020) Mechanism-of-Action Classification of Antibiotics by Global Transcriptome Profiling. Antimicrob Agents Chemother. Feb 21 64(3):e01207-19. PMID: 31907190 [PDF]

  9. Öster C, Walkowiak GP, Hughes DE, Spoering AL, Peoples AJ, Catherwood AC, Tod JA, Lloyd AJ, Herrmann T, Lewis K, Dowson CG, Lewandowski JR (2018) Structural studies suggest aggregation as one of the modes of action for teixobactin. Chem Sci. Sep 20 9(47):8850-8859. PMID: 30627403 [PDF]

  10. Jones MB, Nierman WC, Shan Y, Frank BC, Spoering A, Ling L, Peoples A, Zullo A, Lewis K, Nelson KE (2017) Reducing the bottleneck in discovery of novel antibiotics. Microbial Ecology. 73(3):658-667. PMID: 27896376. [PDF]

  11. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A , Schäberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR , Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K (2015) A novel antibiotic kills pathogens without detectable resistance, Nature, 07 January 2015, doi:10.1038/nature14098. [PDF]

  12. Gavrish E, Sit CS, Cao S, Kandror O, Spoering A, Peoples A, Ling L, Fetterman A, Hughes D, Bissell A, Torrey H, Akopian T, Mueller A, Epstein S, Goldberg A, Clardy J, Lewis K (2014) Lassomycin, a ribosomally synthesized cyclic peptide, kills Mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2. Chem Biol. 21(4):509-18. [PDF]

  13. Buerger S, Spoering AL, Gavrish E, Leslin C, Ling LL, and Epstein S. (2012) Microbial scout hypothesis and microbial discovery. AEM. 78(9):3229-33. [PDF]

  14. Buerger S, Gavrish E, Spoering AL, Leslin C, Ling L,L. and Epstein S. (2012) Microbial scout hypothesis, stochastic exit from dormancy, and the nature of slow growers. AEM. 78(9): 3221-8. [PDF]

  15. Lewis, K, Epstein, S, D’Onofrio, A, and Ling, LL (2010) Uncultured microorganisms as a source of secondary metabolites. J. Antibiot (Tokyo) 63(8):468-76.

  16. Zhang, Q, Peoples, AJ, Rothfeder, M T, Millett ,WP, Pescatore BC, Ling LL, and Moore CM (2009) Isofuranonaphthoquinone produced by an actinoplanes isolate. J. Nat. Prod. 72(6):1213-5. [PDF]

  17. Peoples, AJ, Zhang, Q, Millett, WP, Rothfeder, MT, Pescatore, BC, Madden, AA, Ling LL, and Moore CM (2008) Neocitreamicins I and II, novel antibiotics with activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. J. Antibiot (Tokyo) 61(7):457-63. [PDF]

  18. Kaeberlein, T, Lewis, K, and Epstein, SS (2002) Isolating "Uncultivable" Microorganisms in Pure Culture in a Simulated Natural Environment. Science 296:1127-1129. [PDF]