Institution
NovoBiotic Pharmaceuticals
Company•Cambridge, Massachusetts, United States•
About: NovoBiotic Pharmaceuticals is a company organization based out in Cambridge, Massachusetts, United States. It is known for research contribution in the topics: Teixobactin & Lipid II. The organization has 30 authors who have published 21 publications receiving 2444 citations.
Topics: Teixobactin, Lipid II, Antibiotics, Methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis
Papers
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TL;DR: The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance, as well as several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors.
Abstract: Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.
1,964 citations
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TL;DR: It is shown that lassomycin binds to a highly acidic region of the ClpC1 ATPase complex and markedly stimulates its ATPase activity without stimulating ClpP1P2-catalyzed protein breakdown, which is essential for viability of mycobacteria.
301 citations
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TL;DR: The co-culture approach has led to the identification of the first class of growth factors for uncultured bacteria, iron-chelating siderophores, and new cultivation approaches allow for the exploitation of the secondary metabolite potential of the previously inaccessible microorganisms.
Abstract: The vast majority of microbial species are ‘uncultured’ and do not grow under laboratory conditions. This has led to the development of a number of methods to culture these organisms in a simulated natural environment. Approaches include placing cells in chambers that allow diffusion of compounds from the natural environment, traps enclosed with porous membranes that specifically capture organisms forming hyphae—actinobacteria and microfungi, and growth in the presence of cultivable helper species. Repeated cultivation in situ produces domesticated variants that can grow on regular media in vitro, and can be scaled up for secondary metabolite production. The co-culture approach has led to the identification of the first class of growth factors for uncultured bacteria, iron-chelating siderophores. It appears that many uncultured organisms from diverse taxonomical groups have lost the ability to produce siderophores, and depend on neighboring species for growth. The new cultivation approaches allow for the exploitation of the secondary metabolite potential of the previously inaccessible microorganisms.
166 citations
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TL;DR: This work moved cultivation into the microbes' natural habitat by placing cells taken from varying environmental samples into diffusion chambers, which are then returned to nature for incubation, and called this cultivation platform the 'isolation chip', or 'ichip'.
Abstract: Most microbial species remain uncultivated, and modifying artificial nutrient media brings only an incremental increase in cultivability We reasoned that an alternative way to cultivate species with unknown requirements is to use naturally occurring combinations of growth factors To achieve this, we moved cultivation into the microbes' natural habitat by placing cells taken from varying environmental samples into diffusion chambers, which are then returned to nature for incubation By miniaturizing the chambers and placing only one to several cells into each chamber, we can grow and isolate microorganisms in axenic culture in one step We call this cultivation platform the 'isolation chip', or 'ichip' This platform has been shown to increase microbial recovery from 5- to 300-fold, depending on the study Furthermore, it provides access to a unique set of microbes that are inaccessible by standard cultivation Here we provide a simple protocol for building and applying ichips for environmental cultivation of soil bacteria as an example; the protocol consists of (i) preparing the ichip; (ii) collecting an environmental sample; (iii) serially diluting cells and loading them into the ichip; (iv) returning the ichip to the environment for incubation; (v) retrieving the ichip and harvesting grown material; and (vi) domestication of the ichip-derived colonies for growth in the laboratory The ichip's full assembly and deployment is a relatively simple procedure that, with experience, takes ∼2-3 h After in situ incubation, retrieval of the ichip and processing of its contents will take ∼1-4 h, depending on which specific procedures are used
136 citations
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TL;DR: It is shown that a range of microorganisms, including environmental species, Escherichia coli, and Mycobacterium smegmatis, indeed wake up in a seemingly stochastic manner and independently of environmental conditions, even in the longest incubations conducted, and genuine slow growth appears to be less significant than previously believed.
Abstract: We recently proposed a scout model of the microbial life cycle (S. S. Epstein, Nature 457:1083, 2009), the central element of which is the hypothesis that dormant microbial cells wake up into active (so-called scout) cells stochastically, independently of environmental cues. Here, we check the principal prediction of this hypothesis: under growth-permissive conditions, dormant cells initiate growth at random time intervals and exhibit no species-specific lag phase. We show that a range of microorganisms, including environmental species, Escherichia coli, and Mycobacterium smegmatis, indeed wake up in a seemingly stochastic manner and independently of environmental conditions, even in the longest incubations conducted (months to years long). As is implicit in the model, most of the cultures we obtained after long incubations were not inherently slow growers. Of the environmental isolates that required ≥7 months to form visible growth, only 5% needed an equally long incubation upon subculturing, with the majority exhibiting regrowth within 24 to 48 h. This apparent change was not a result of adaptive mutation; rather, most microbial species that appear to be slow growers were in fact fast growers with a delayed initiation of division. Genuine slow growth thus appears to be less significant than previously believed. Random, low-frequency exit from the nongrowing state may be a key element of a general microbial survival strategy, and the phylogenetic breadth of the organisms exhibiting such exit indicates that it represents a general phenomenon. The stochasticity of awakening can also provide a parsimonious explanation to several microbiological observations, including the apparent randomness of latent infections and the existence of viable-but-nonculturable cells (VBNC).
113 citations
Authors
Showing all 30 results
Name | H-index | Papers | Citations |
---|---|---|---|
Kim Lewis | 82 | 199 | 31579 |
Slava S. Epstein | 42 | 117 | 9270 |
Linos Lazarides | 13 | 25 | 2103 |
Amy Spoering | 13 | 23 | 4199 |
Anne A. Madden | 11 | 22 | 379 |
Dallas Hughes | 8 | 16 | 2060 |
Aaron J. Peoples | 8 | 20 | 2065 |
William Millett | 6 | 13 | 1799 |
Victoria Alexandra Steadman | 6 | 11 | 1849 |
Losee L Ling | 5 | 7 | 309 |
Karine G. Poullennec | 4 | 7 | 126 |
Losee Lucy Ling | 3 | 5 | 274 |
Cintia R. Felix | 3 | 3 | 1724 |
Ashley Zullo | 3 | 5 | 1745 |
Anthony Nitti | 3 | 10 | 1740 |