Natural product growth inhibitors of Mycobacterium tuberculosis

2007 ◽  
Vol 24 (2) ◽  
pp. 278-297 ◽  
Author(s):  
Brent R. Copp ◽  
A. Norrie Pearce
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Growth Inhibitors

scholarly journals A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466

Marine Drugs ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 149 ◽  
Author(s):  
Yan Xie ◽  
Yunjiang Feng ◽  
Angela Di Capua ◽  
Tin Mak ◽  
Garry W. Buchko ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Natural Product ◽  
Covalent Bond ◽  
Pure Compound ◽  
Active Components ◽  
Ligand Complex ◽  
Mycobacterium Tuberculosis H37rv ◽  
Compound Libraries

In recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach combines the strengths of the PDD and TDD approaches. Phenotypic screening is conducted initially to detect cellular active components and the hits are then screened against a panel of putative targets. This PhenoTarget protocol can be equally applied to pure compound libraries as well as natural product fractions. Here we described the use of the PhenoTarget approach to identify an anti-tuberculosis lead compound. Fractions from Polycarpa aurata were identified with activity against Mycobacterium tuberculosis H37Rv. Native magnetic resonance mass spectrometry (MRMS) against a panel of 37 proteins from Mycobacterium proteomes showed that a fraction from a 95% ethanol re-extraction specifically formed a protein-ligand complex with Rv1466, a putative uncharacterized Mycobacterium tuberculosis protein. The natural product responsible was isolated and characterized to be polycarpine. The molecular weight of the ligand bound to Rv1466, 233 Da, was half the molecular weight of polycarpine less one proton, indicating that polycarpine formed a covalent bond with Rv1466.

scholarly journals Identification of cyclic hexapeptides natural products with inhibitory potency against Mycobacterium tuberculosis

2018 ◽  
Author(s):  
Sheo B. Singh ◽  
Joshua Odingo ◽  
Mai A. Bailey ◽  
Bjorn Sunde ◽  
Aaron Korkegian ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Resistant Mutant ◽  
Significant Activity ◽  
Human Pathogen ◽  
Inhibitory Potency ◽  
Structure Activity ◽  
Cyclic Hexapeptides ◽  
Natural Product Compounds ◽  
Related Compounds

AbstractA set of ∼500 purified natural product compounds was screened for inhibition against the human pathogen Mycobacterium tuberculosis. A series of cyclic hexapeptides with anti-tubercular activity was identified. Five analogs from a set of sixteen closely related compounds were active, with minimum inhibitory concentrations ranging from 2.3-8.9 μM. Eleven structural analogs had no significant activity (MIC > 20 μM) demonstrating structure activity relationship. Sequencing of resistant mutant isolates failed to identify changes accounting for the resistance phenotype.

scholarly journals Novel Antimicrobials from Uncultured Bacteria Acting against Mycobacterium tuberculosis

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Jeffrey Quigley ◽  
Aaron Peoples ◽  
Asel Sarybaeva ◽  
Dallas Hughes ◽  
Meghan Ghiglieri ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Protein Secretion ◽  
Specific Activity ◽  
Therapeutic Options ◽  
Content Type ◽  
Natural Product Discovery ◽  
Uncultured Bacteria ◽  
New Compounds ◽  
Drug Resistant Strains

ABSTRACT Mycobacterium tuberculosis, which causes tuberculosis (TB), is estimated to infect one-third of the world’s population. The overall burden and the emergence of drug-resistant strains of Mycobacterium tuberculosis underscore the need for new therapeutic options against this important human pathogen. Our recent work demonstrated the success of natural product discovery in identifying novel compounds with efficacy against Mycobacterium tuberculosis. Here, we improve on these methods by combining improved isolation and Mycobacterium tuberculosis selective screening to identify three new anti-TB compounds: streptomycobactin, kitamycobactin, and amycobactin. We were unable to obtain mutants resistant to streptomycobactin, and its target remains to be elucidated. We identify the target of kitamycobactin to be the mycobacterial ClpP1P2C1 protease and confirm that kitamycobactin is an analog of the previously identified compound lassomycin. Further, we identify the target of amycobactin to be the essential protein secretion pore SecY. We show further that amycobactin inhibits protein secretion via the SecY translocon. Importantly, this inhibition is bactericidal to nonreplicating Mycobacterium tuberculosis. This is the first compound, to our knowledge, that targets the Sec protein secretion machinery in Mycobacterium tuberculosis. This work underscores the ability of natural product discovery to deliver not only new compounds with activity against Mycobacterium tuberculosis but also compounds with novel targets. IMPORTANCE Decreasing discovery rates and increasing resistance have underscored the need for novel therapeutic options to treat Mycobacterium tuberculosis infection. Here, we screen extracts from previously uncultured soil microbes for specific activity against Mycobacterium tuberculosis, identifying three novel compounds. We further define the mechanism of action of one compound, amycobactin, and demonstrate that it inhibits protein secretion through the Sec translocation machinery.

The Natural Product Cyclomarin Kills Mycobacterium Tuberculosis by Targeting the ClpC1 Subunit of the Caseinolytic Protease

2011 ◽  
Vol 50 (26) ◽  
pp. 5889-5891 ◽  
Author(s):  
Esther K. Schmitt ◽  
Meliana Riwanto ◽  
Vasan Sambandamurthy ◽  
Silvio Roggo ◽  
Charlotte Miault ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Caseinolytic Protease

Anti-HIV natural product (+)-calanolide A is active against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis

2004 ◽  
Vol 12 (5) ◽  
pp. 1199-1207 ◽  
Author(s):  
Ze-Qi Xu ◽  
William W Barrow ◽  
William J Suling ◽  
Louise Westbrook ◽  
Esther Barrow ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Anti Hiv ◽  
Calanolide A

scholarly journals Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis

2018 ◽  
Vol 72 (2) ◽  
pp. 263-274.e5 ◽  
Author(s):  
Hamed Mosaei ◽  
Vadim Molodtsov ◽  
Bernhard Kepplinger ◽  
John Harbottle ◽  
Christopher William Moon ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Natural Product ◽  
Mode Of Action
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