Inhibitors Selective for Mycobacterial versus Human Proteasomes

Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, USA.
Nature (Impact Factor: 41.46). 09/2009; 461(7264):621-6. DOI: 10.1038/nature08357
Source: PubMed


Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M. tuberculosis and act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.

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    • "These results are in agreement with those of earlier studies in E. coli (Hyduke et al., 2007; Ren et al., 2008). Earlier DETA-NO was used to create a nitro-oxidative stress that limits the replication of M. tuberculosis (Lin et al., 2009). "

    Full-text · Dataset · Mar 2015
    • "To the multiple layers of Mtb's defenses, the present observations add what may be a defense of last resort: sequestration of proteins whose irreversible accumulation of carbonyls leads to misfolding. Misfolding may make proteins as dangerous as they are resistant to degradation by the two major chambered proteases of Mtb, ClpP1P2 (Raju et al., 2012) and the proteasome (Darwin et al., 2003; Lin et al., 2009). IOPs that are resistant to degradation can accumulate as potentially proteotoxic species. "
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    ABSTRACT: Mycobacterium tuberculosis (Mtb) defends itself against host immunity and chemotherapy at several levels, including the repair or degradation of irreversibly oxidized proteins (IOPs). To investigate how Mtb deals with IOPs that can neither be repaired nor degraded, we used new chemical and biochemical probes and improved image analysis algorithms for time-lapse microscopy to reveal a defense against stationary phase stress, oxidants, and antibiotics-the sequestration of IOPs into aggregates in association with the chaperone ClpB, followed by the asymmetric distribution of aggregates within bacteria and between their progeny. Progeny born with minimal IOPs grew faster and better survived a subsequent antibiotic stress than their IOP-burdened sibs. ClpB-deficient Mtb had a marked recovery defect from stationary phase or antibiotic exposure and survived poorly in mice. Treatment of tuberculosis might be assisted by drugs that cripple the pathway by which Mtb buffers, sequesters, and asymmetrically distributes IOPs. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jan 2015 · Cell Host & Microbe
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    • "In 2009, Lin et al. described the synthesis of oxathiazol-2-ones derived from a HTS targeting the Mtb proteasome (42). Proteasomes represent an important class of complex enzymes involved in protein degradation and have been investigated as potential targets for the treatment of several human diseases. "
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    ABSTRACT: Abstract Tuberculosis (TB) represents a major public health problem. The growing number of (extensively) multi-drug resistance cases indicates that there is an urgent need for discovery of new anti-TB entities, addressed towards new and specific targets, and continuous development of fast and efficient synthetic strategies to access them easily. Microwave-assisted chemistry is well suited for small-scale laboratory synthetic work, allowing full control of reaction conditions, such as temperature, pressure, and time. Microwave-assisted high-speed organic synthesis is especially useful in the lead optimization phase of drug discovery. To illustrate the advantages of modern microwave heating technology, we herein describe applications and approaches that have been useful for the synthesis of new drug-like anti-TB compounds.
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