Targeting the Proteostasis Network for Mycobacterial Drug Discovery

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Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world’s deadliest infectious diseases and urgently requires new antibiotics to treat drug-resistant strains and to decrease the duration of therapy. During infection, Mtb encounters numerous stresses associated with host immunity, including hypoxia, reactive oxygen and nitrogen species, mild acidity, nutrient starvation, and metal sequestration and intoxication. The Mtb proteostasis network, composed of chaperones, proteases, and a eukaryotic-like proteasome, provides protection from stresses and chemistries of host immunity by maintaining the integrity of the mycobacterial proteome. In this Review, we explore the proteostasis network as a noncanonical target for antibacterial drug discovery.

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Most cited references 197

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Molecular chaperones in protein folding and proteostasis.

F Ulrich Hartl, Andreas Bracher, Manajit Hayer-Hartl (2011)

Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.

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A common mechanism of cellular death induced by bactericidal antibiotics.

Michael A Kohanski, Daniel Dwyer, Boris Hayete … (2007)

Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.

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Hsp70 chaperones: Cellular functions and molecular mechanism

M P Mayer, B. Bukau (2005)

Abstract. Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.

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Author and article information

Journal

Journal ID (nlm-ta): ACS Infect Dis

Journal ID (iso-abbrev): ACS Infect Dis

Journal ID (publisher-id): id

Journal ID (coden): aidcbc

Title: ACS Infectious Diseases

Publisher: American Chemical Society

ISSN (Electronic): 2373-8227

Publication date (Electronic): 21 February 2018

Publication date (Print): 13 April 2018

Volume: 4

Issue: 4 , Drug Discovery for Global Health

Pages: 478-498

Affiliations

[1]Department of Microbiology and Immunology, Weill Cornell Medicine , 413 East 69th Street, New York, New York 10021, United States

Author notes

[* ]E-mail: bsg2001@ 123456med.cornell.edu . Phone: 646-962-6209.

Article

DOI: 10.1021/acsinfecdis.7b00231

PMC ID: 5902792

PubMed ID: 29465983

SO-VID: 67fdf60d-a118-4085-bd86-699661dd318d

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This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.

History

Date received : 14 November 2017

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document-id-old-9 id7b00231

document-id-new-14 id-2017-00231t

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Keywords: proteostasis,proteolysis,chaperones,proteasome,proteases,protein aggregation,protein folding,protein misfolding,proteostasis network,mycobacterium tuberculosis,antibiotics,host immunity

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Keywords: proteostasis, proteolysis, chaperones, proteasome, proteases, protein aggregation, protein folding, protein misfolding, proteostasis network, mycobacterium tuberculosis, antibiotics, host immunity

Targeting the Proteostasis Network for Mycobacterial Drug Discovery

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Abstract

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Drug Repurposing Research Collection

Most cited references 197

Molecular chaperones in protein folding and proteostasis.

A common mechanism of cellular death induced by bactericidal antibiotics.

Hsp70 chaperones: Cellular functions and molecular mechanism

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