Image: Eleftheria terrae, the Gram-negative bacterium that produces teixobactin
SEM picture by William Fowle, Northeastern University
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.
Teixobactin. Teixobactin is the first member of a novel class of peptidoglycan synthesis inhibitors (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 binds to 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 modified. 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.
Novo10. Novo10 is a preclinical lead compound for oncology. This novel macrocycle shows excellent potency against the 60 human tumor cell line panel of the National Cancer Institute, and efficacy in a murine xenograft model. Novo10 is a highly selective stabilizer of G-quadruplex structures (G4s). G4s are transient, four-stranded DNA structures found in telomeres and promoter sequences of oncogenes, and are believed to be critical for cellular processes such as gene expression, replication and cell division. Stabilization (trapping) of these features by small molecule ligands halts runaway cell proliferation, and thus represents a promising new mode of action for oncology drugs.
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.
- 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. [Abstract]
- 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.
- 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]
- 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]
- 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.
- 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]
- 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]
- Kaeberlein, T, Lewis, K, and Epstein, SS (2002) Isolating "Uncultivable" Microorganisms in Pure Culture in a Simulated Natural Environment. Science 296:1127-1129. [PDF]