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

Sheo B. Singh, Joshua Odingo, Mai A. Bailey, Bjorn Sunde, Aaron Korkegian, Theresa O’Malley, Yulia Ovechkina, Thomas R. Ioerger, James C. Sacchettini, Katherine Young, David B. Olsen, Tanya Parish
doi: https://doi.org/10.1101/279307
Sheo B. Singh
1Merck & Co., Inc., Infectious Diseases, 770 Sumneytown Pike, West Point PA, 19486, USA
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Joshua Odingo
2TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, WA 98102, USA
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Mai A. Bailey
2TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, WA 98102, USA
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Bjorn Sunde
2TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, WA 98102, USA
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Aaron Korkegian
2TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, WA 98102, USA
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Theresa O’Malley
1Merck & Co., Inc., Infectious Diseases, 770 Sumneytown Pike, West Point PA, 19486, USA
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Yulia Ovechkina
2TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, WA 98102, USA
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Thomas R. Ioerger
3Texas A&M University, College Station, TX, USA
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James C. Sacchettini
3Texas A&M University, College Station, TX, USA
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Katherine Young
1Merck & Co., Inc., Infectious Diseases, 770 Sumneytown Pike, West Point PA, 19486, USA
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David B. Olsen
1Merck & Co., Inc., Infectious Diseases, 770 Sumneytown Pike, West Point PA, 19486, USA
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Tanya Parish
2TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue E, Suite 400, WA 98102, USA
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  • For correspondence: tanya.parish@idri.org
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Abstract

A 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.

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Posted March 10, 2018.
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Identification of cyclic hexapeptides natural products with inhibitory potency against Mycobacterium tuberculosis
Sheo B. Singh, Joshua Odingo, Mai A. Bailey, Bjorn Sunde, Aaron Korkegian, Theresa O’Malley, Yulia Ovechkina, Thomas R. Ioerger, James C. Sacchettini, Katherine Young, David B. Olsen, Tanya Parish
bioRxiv 279307; doi: https://doi.org/10.1101/279307
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Identification of cyclic hexapeptides natural products with inhibitory potency against Mycobacterium tuberculosis
Sheo B. Singh, Joshua Odingo, Mai A. Bailey, Bjorn Sunde, Aaron Korkegian, Theresa O’Malley, Yulia Ovechkina, Thomas R. Ioerger, James C. Sacchettini, Katherine Young, David B. Olsen, Tanya Parish
bioRxiv 279307; doi: https://doi.org/10.1101/279307

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