Christopher M DeMott1, Roxie Girardin2, Jacqueline Cobbert1, Sergey Reverdatto1, David S Burz1, Kathleen McDonough2,3, Alexander Shekhtman1. 1. Department of Chemistry , University at Albany, State University of New York , Albany , New York 12222 , United States. 2. Wadsworth Center , New York Department of Health , Albany , New York 12208 , United States. 3. Department of Biomedical Sciences , University at Albany, State University of New York , Albany , New York 12222 , United States.
Abstract
In-cell NMR spectroscopy was used to screen for drugs that disrupt the interaction between prokaryotic ubiquitin like protein, Pup, and mycobacterial proteasome ATPase, Mpa. This interaction is critical for Mycobacterium tuberculosis resistance against nitric oxide (NO) stress; interruption of this process was proposed as a mechanism to control latent infection. Three compounds isolated from the NCI Diversity set III library rescued the physiological proteasome substrate from degradation suggesting that the proteasome degradation pathway was selectively targeted. Two of the compounds bind to Mpa with sub-micromolar to nanomolar affinity, and all three exhibit potency toward mycobacteria comparable to antibiotics currently available on the market, inhibiting growth in the low micromolar range.
In-cell NMR spectroscopy was used to screen for drugs that disrupt the interaction between prokaryotic ubiquitin like protein, Pup, and mycobacterial proteasome pan class="Chemical">ATPase, Mpan>. This interaction is critical for n>n class="Species">Mycobacterium tuberculosis resistance against nitric oxide (NO) stress; interruption of this process was proposed as a mechanism to control latent infection. Three compounds isolated from the NCI Diversity set III library rescued the physiological proteasome substrate from degradation suggesting that the proteasome degradation pathway was selectively targeted. Two of the compounds bind to Mpa with sub-micromolar to nanomolar affinity, and all three exhibit potency toward mycobacteria comparable to antibiotics currently available on the market, inhibiting growth in the low micromolar range.
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Authors: Jacqueline D Cobbert; Christopher DeMott; Subhabrata Majumder; Eric A Smith; Sergey Reverdatto; David S Burz; Kathleen A McDonough; Alexander Shekhtman Journal: Sci Rep Date: 2015-03-24 Impact factor: 4.379