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. Using all our unique culturing technologies, we have built a strain collection of over 64,000 microbial isolates.
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.
Novo29. Novo29 is a new antimicrobial compound discovered using NovoBiotic’s proprietary culturing platform. Novo29 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 Novo29 failed to generate resistance. However, Novo29 is much smaller than teixobactin, and shows different binding characteristics to cell wall precursors. Novo29 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.
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.
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]