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.
Highlights
Using aggregated luciferase as a model protein substrate, biochemical reconstitution of this proteostasis network consisting of Mycobacterium tuberculosis (Mtb) DnaK, cofactors, ClpB, and Hsp[20] showed that GrpE and at least one DnaJ−protein is required for luciferase refolding and that DnaJ1 and DnaJ2 exhibit nonredundant roles in protein folding.[65]
Some individual components of the proteostasis network, such as the proteasome, are vulnerable to selective inhibition over their eukaryotic counterparts,[40] and we anticipate that species-selective inhibitors could be selected for most of the components of the pathway
Targeting the proteostasis network will prevent Mtb from repairing damage to mycobacterial proteins that had already been inflicted by the host
Summary
As oxygen, carbon monoxide, carbon dioxide, and nitric oxide, and host immune effectors, encourages Mtb to proliferate, cease replicating and remain metabolically active, remain metabolically active and nonculturable, die by starvation for essential nutrients, or die after insult by host immune effectors.[5]. Microscopy studies in live mycobacteria have shown that ClpB and DnaK are recruited to a fluorescently tagged aggregating protein sequence (ELK16) and that tagged chaperones form foci that colocalize with these aggregates.[48,71] Using aggregated luciferase as a model protein substrate, biochemical reconstitution of this proteostasis network consisting of Mtb DnaK, cofactors, ClpB, and Hsp[20] showed that GrpE and at least one DnaJ−protein is required for luciferase refolding and that DnaJ1 and DnaJ2 exhibit nonredundant roles in protein folding.[65] The in vitro requirements for these proteins in refolding reactions are consistent with grpE’s essentiality and dnaJ1 and dnaJ2’s synthetic lethality in Msm. Differences in the activity of mycobacterial DnaJ proteins were evident in ATPase assays that showed DnaJ1 and DnaJ2 activate ATP hydrolysis by DnaK in the presence of GrpE to different degrees. The GroE system binds hydrophobic patches on polypeptides that are exposed during translation and helps stabilize folding intermediates by encasing them in a central channel.[46,80] The GroE system helps fold newly synthesized proteins that TF and DnaK cannot
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