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 Heck- and Suzuki-coupling approaches to novel hydroquinone inhibitors of calcium ATPase

2019 ◽  
Vol 15 ◽  
pp. 971-975 ◽  
Author(s):  
Robert J Kempton ◽  
Taylor A Kidd-Kautz ◽  
Soizic Laurenceau ◽  
Stefan Paula
Keyword(s):  
Prostate Cancer ◽  
Endoplasmic Reticulum ◽  
Natural Product ◽  
Suzuki Coupling ◽  
Calcium Atpase ◽  
Prostate Cancer Cells ◽  
Inhibitory Potency ◽  
Suitable Candidate ◽  
Endoplasmic Reticulum Calcium ◽  
Related Compounds

In this study, we explored Heck- and Suzuki-coupling methodology to modify the template 2,5-di-tert-butylhydroquinone (BHQ, 2), an inhibitor of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). We found that by utilizing Suzuki coupling, we could successfully attach a six-carbon tether to BHQ that terminated in a leucine moiety to obtain target 14. Similar to related compounds based on the structure of the natural product thapsigargin, 14 displayed inhibitory potency against SERCA activity. This makes 14 a suitable candidate for the future attachment of a deactivating peptide to convey specificity for prostate cancer cells.

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

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Sheo B. Singh ◽  
Joshua Odingo ◽  
Mai A. Bailey ◽  
Bjorn Sunde ◽  
Aaron Korkegian ◽  
...  
Keyword(s):  
Natural Products ◽  
Mycobacterium Tuberculosis ◽  
Inhibitory Potency ◽  
Cyclic Hexapeptides

Synthesis of Norfijimycin A with Activity against Mycobacterium tuberculosis

2017 ◽  
Vol 70 (2) ◽  
pp. 229 ◽  
Author(s):  
Alexander Stoye ◽  
Gayathri Nagalingam ◽  
Warwick J. Britton ◽  
Richard J. Payne
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Mycobacterium Tuberculosis ◽  
Total Synthesis ◽  
Natural Product ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Marine Natural Product ◽  
Significant Activity ◽  
Methyl Group ◽  
Cyclic Depsipeptide

The total synthesis of norfijimycin A, a simplified analogue of the marine natural product fijimycin A, is described. Fijimycin A is a cyclic depsipeptide that has been shown to possess activity against methicillin-resistant Staphylococcus aureus. The natural product contains a rare N,β-dimethyl leucine unit with unknown stereochemistry at the β-carbon. To evaluate the importance of the β-methyl group for antimicrobial activity, we introduced N-methyl leucine into the natural product scaffold. The resulting norfijimycin A was shown to possess significant activity against Mycobacterium tuberculosis, the etiological agent of tuberculosis.

Current insights into the chemistry and antitubercular potential of benzimidazole and imidazole derivatives

2020 ◽  
Vol 20 ◽  
Author(s):  
Deepa Parwani ◽  
Sushanta Bhattacharya ◽  
Akash Rathore ◽  
Chaitali Mallick ◽  
Vivek Asati ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Multi Drug Resistance ◽  
Benzimidazole Derivatives ◽  
Duration Of Treatment ◽  
Structure Activity ◽  
Mdr Tb ◽  
Low Toxicity ◽  
Extensively Drug Resistance ◽  
Improved Characteristics

: Tuberculosis is a disease caused by Mycobacterium tuberculosis (Mtb), affecting millions of people worldwide. The emergence of drug resistance is a major problem in the successful treatment of tuberculosis. Due to the commencement of MDR-TB (multi-drug resistance) and XDR-TB (extensively drug resistance), there is a crucial need for the development of novel anti-tubercular agents with improved characteristics such as low toxicity, enhanced inhibitory activity and short duration of treatment. In this direction, various heterocyclic compounds have been synthesized and screened against Mycobacterium tuberculosis. Among them, benzimidazole and imidazole containing derivatives found to have potential anti-tubercular activity. The present review focuses on various imidazole and benzimidazole derivatives (from 2015-2019) with their structure activity relationships in the treatment of tuberculosis.

New Groups of Potential Antituberculotics: Bis(1-aryltetrazol-5-yl) Disulfides. Structure Activity Relationship

1994 ◽  
Vol 59 (1) ◽  
pp. 234-238 ◽  
Author(s):  
Karel Waisser ◽  
Jiří Kuneš ◽  
Alexandr Hrabálek ◽  
Želmíra Odlerová
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Antimycobacterial Activity ◽  
Activity Relationship ◽  
Active Derivative ◽  
Structure Activity ◽  
Medium Activity ◽  
Substituent Constants ◽  
Atypical Strains

Oxidation of 1-aryltetrazole-5-thiols afforded bis(1-aryltetrazol-5-yl) disulfides. The compounds were tested for antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, M. avium and M. fortuitum. In the case of M. tuberculosis, the logarithm of minimum inhibitory concentration showed a parabolic dependence on hydrophobic substituent constants. Although the compounds exhibited low to medium activity, the most active derivative, bis(4-chlorophenyltetrazol-5-yl) disulfide (III) was more effective against atypical strains than are the commercial tuberculostatics used as standards.

scholarly journals Moxifloxacin Activates the SOS Response in Mycobacterium tuberculosis in a Dose- and Time-Dependent Manner

2021 ◽  
Vol 9 (2) ◽  
pp. 255
Author(s):  
Angelo Iacobino ◽  
Giovanni Piccaro ◽  
Manuela Pardini ◽  
Lanfranco Fattorini ◽  
Federico Giannoni
Keyword(s):  
Gene Expression ◽  
Mycobacterium Tuberculosis ◽  
Physiological State ◽  
Transcriptional Response ◽  
Sos Response ◽  
Resistant Mutant ◽  
Time Dependent ◽  
Dependent Manner ◽  
Gyra Gene ◽  
Drug Concentrations

Previous studies on Escherichia coli demonstrated that sub-minimum inhibitory concentration (MIC) of fluoroquinolones induced the SOS response, increasing drug tolerance. We characterized the transcriptional response to moxifloxacin in Mycobacterium tuberculosis. Reference strain H37Rv was treated with moxifloxacin and gene expression studied by qRT-PCR. Five SOS regulon genes, recA, lexA, dnaE2, Rv3074 and Rv3776, were induced in a dose- and time-dependent manner. A range of moxifloxacin concentrations induced recA, with a peak observed at 2 × MIC (0.25 μg/mL) after 16 h. Another seven SOS responses and three DNA repair genes were significantly induced by moxifloxacin. Induction of recA by moxifloxacin was higher in log-phase than in early- and stationary-phase cells, and absent in dormant bacilli. Furthermore, in an H37Rv fluoroquinolone-resistant mutant carrying the D94G mutation in the gyrA gene, the SOS response was induced at drug concentrations higher than the mutant MIC value. The 2 × MIC of moxifloxacin determined no significant changes in gene expression in a panel of 32 genes, except for up-regulation of the relK toxin and of Rv3290c and Rv2517c, two persistence-related genes. Overall, our data show that activation of the SOS response by moxifloxacin, a likely link to increased mutation rate and persister formation, is time, dose, physiological state and, possibly, MIC dependent.

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 Transposition of Tn5367 in Mycobacterium marinum, Using a Conditionally Recombinant Mycobacteriophage

2003 ◽  
Vol 185 (5) ◽  
pp. 1745-1748 ◽  
Author(s):  
Jan Rybniker ◽  
Martina Wolke ◽  
Christiane Haefs ◽  
Georg Plum
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Skin Infection ◽  
Model Organism ◽  
Transposon Mutagenesis ◽  
Mycobacterium Marinum ◽  
Close Relative ◽  
Mutant Library ◽  
Human Pathogen ◽  
Valid Model ◽  
Highly Efficient

ABSTRACT Mycobacterium marinum is a close relative of the obligate human pathogen Mycobacterium tuberculosis. As with M. tuberculosis, M. marinum causes intracellular infection of poikilothermic vertebrates and skin infection in humans. It is considered a valid model organism for the study of intracellular pathogenesis of mycobacteria. Low transformation efficiencies for this species have precluded approaches using mutant libraries in pathogenesis studies. We have adapted the conditionally replicating mycobacteriophage phAE94, originally developed as a transposon mutagenesis tool for M. tuberculosis, to meet the specific requirements of M. marinum. Conditions permissive for phage replication in M. tuberculosis facilitated highly efficient transposon delivery in M. marinum. Using this technique we succeeded in generating a representative mutant library of this species, and we conclude that TM4-derived mycobacteriophages are temperature-independent suicide vectors for M. marinum.

Sign in / Sign up

Export Citation Format

Share Document