Discovery and Characterization of the Tuberculosis Drug Lead Ecumicin

Gao, Wei; Kim, Jin Yong; Chen, Shao-Nong; Cho, Sang Hyun; Choi, Joon‐Hwan; Jaki, Birgit U.; Jin, Ying; Lankin, David C.; Lee, Ji Ean; Lee, Sun Young; McAlpine, James B.; Napolitano, José G.; Franzblau, Scott G.; Suh, Joo Won; Pauli, Guido F.

doi:10.1021/ol5026603

Cited by 52 publications

(62 citation statements)

References 11 publications

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“…1), a macrocyclic tridecapeptide, was isolated from strain MJM5123, which was prioritized based on the strong activity in the lipophilic fractions of the mycelial methanolic extract against both replicating and nonreplicating M. tuberculosis H37Rv as well as strains that are resistant to the existing actinomycete-derived antibiotics (21)(22)(23).…”

Section: High-throughput Screeningmentioning

confidence: 99%

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Gao

Kim

Anderson

et al. 2015

Antimicrob Agents Chemother

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162

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Mycobacterium tuberculosis is the cause of one of the most deadly diseases of mankind, and despite the availability of effective treatments, tuberculosis (TB) remains a major public health threat. The difficult challenges in treating multiple-drugresistant (MDR) and extensively drug-resistant (XDR) TB and the importance of shortening the duration of treatment to improve patients' compliance make the discovery of new anti-TB drugs imperative (1-5). Attempts to discover new TB drugs and targets via large-scale screening against intact mycobacteria have largely been confined to synthetic compound libraries and to date have yielded only one new clinical TB drug, the diarylquinoline bedaquiline (6, 7). Although very potent, to be of maximum benefit, bedaquiline, a diarylquinoline, and nitroimidazoles (8) require new companion drugs to be used in a multidrug regimen.While the intensive search for antibiotics from soil microorganisms in the mid-20th century yielded several clinically useful TB drugs, the pathogenic nature of M. tuberculosis and its extremely slow growth rate did not allow classical agar diffusion tests and excluded M. tuberculosis from the initial target panel. The discovery of TB drugs of natural origin at that time therefore relied upon the detection of activity against nonmycobacteria in agar diffusion assays followed by bioassay-guided isolation of the active principle, again using nonmycobacteria. Activity against M. tuberculosis was only assessed once the active principle was purified.Because M. tuberculosis is uniquely susceptible to a number of antimicrobial agents, a high-throughput screening (HTS) of actinomycete extracts directly against the virulent H37Rv strain was conducted, and this campaign revealed selective anti-TB peptides produced by a genetically distinct Nonomuraea species, strain MJM5123. Here, we describe the activity profile of ecumicin, its efficacy in infected mice, the identification of its molecular target, and the elucidation of its unusual mechanism of action. MATERIALS AND METHODSHigh-throughput screening. Approximately 7,000 actinomycete cultures isolated from Korea, China, Nepal, the Philippines, Vietnam, Antarctica, and the Arctic Circle and maintained at Myongji University, South Korea, were fermented in 20-ml cultures in glucose-soybean starch (GSS) medium (rich medium), Bennett's medium (normal medium), and dextrinyeast-corn steep liquor (DYC) medium (minimal medium) (see Table S1 in the supplemental material). The mycelia and culture medium supernatants were separated and extracted with methanol and ethyl acetate, respectively. Nine extracts were thus generated from each microbial isolate.

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Section: High-throughput Screeningmentioning

confidence: 99%

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Gao

Kim

Anderson

et al. 2015

Antimicrob Agents Chemother

Self Cite

162

224

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“…), Ecumicin (Gao et al . , ). This background jointly inspires the rationale of discovering the anti‐TB agents from different species within genera actinomycetales.…”

Section: Resultsmentioning

confidence: 99%

Antituberculotic activity of actinobacteria isolated from the rare habitats

Hussain

Rather

Bhat

et al. 2017

Lett Appl Microbiol

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The study presents the isolation of rare actinobacteria from untapped sites in the Northwestern Himalayas and their in vitro potential against Mycobacterium tuberculosis for their metabolites. The study revealed that exploring the untapped natural sources as one of the resourceful approaches for the discovery of new natural products. This study also provided strong evidence for the ability of rare and potent actinobacterial strains to produce bioactive compounds with antagonistic activity and these metabolites can be studied for inhibitory potential.

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“…12 Ecumicin exerts potent, selective bactericidal activity against Mtb in vitro (MIC 0.26 μ g/mL), including nonreplicating cells. It also retains activity against isolated multiple-drug-resistant and extensively drug-resistant strains, by virtue of a new mode of action.…”

Section: Resultsmentioning

confidence: 99%

Bioautography with TLC-MS/NMR for Rapid Discovery of Anti-tuberculosis Lead Compounds from Natural Sources

et al. 2016

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While natural products constitute an established source of lead compounds, the classical iterative bioassay-guided isolation process is both time- and labor-intensive and prone to failing to identify active minor constituents. (HP)TLC-bioautography-MS/NMR, which combines cutting-edge microbiological, chromatographic, and spectrometric technologies, was developed to accelerate anti-tuberculosis (TB) drug discovery from natural sources by acquiring structural information at a very early stage of the isolation process. Using the avirulent, bioluminescent Mtb strain mc27000 luxABCDE, three variations of bioautography were evaluated and optimized for sensitivity in detecting anti-TB agents, including established clinical agents and new leads with novel mechanisms of action. Several exemplary applications of this approach to microbial extracts demonstrate its potential as a routine method in anti-TB drug discovery from natural sources.

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Discovery and Characterization of the Tuberculosis Drug Lead Ecumicin

Cited by 52 publications

References 11 publications

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Antituberculotic activity of actinobacteria isolated from the rare habitats

Bioautography with TLC-MS/NMR for Rapid Discovery of Anti-tuberculosis Lead Compounds from Natural Sources

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