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Potent Inhibitors of Mycobacterium tuberculosis Growth Identified by Using in-Cell NMR-based Screening.

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.

SUBMITTER: DeMott CM

PROVIDER: S-EPMC5856640 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Potent Inhibitors of Mycobacterium tuberculosis Growth Identified by Using in-Cell NMR-based Screening.

DeMott Christopher M CM Girardin Roxie R Cobbert Jacqueline J Reverdatto Sergey S Burz David S DS McDonough Kathleen K Shekhtman Alexander A

ACS chemical biology 20180202 3

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 suggest ...[more]

PMID: 29359908

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