Targeting the Proteostasis Network for Mycobacterial Drug Discovery

Overview

Journal ACS Infect Dis

Specialties Infectious Diseases
Microbiology
Pharmacology

Date 2018 Feb 22

PMID 29465983

Citations 32

Authors

Tania J Lupoli

Julien Vaubourgeix

Kristin Burns-Huang

Ben Gold

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Koul A, Dendouga N, Vergauwen K, Molenberghs B, Vranckx L, Willebrords R . Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 2007; 3(6):323-4. DOI: 10.1038/nchembio884. View

Voskuil M, Bartek I, Visconti K, Schoolnik G . The response of mycobacterium tuberculosis to reactive oxygen and nitrogen species. Front Microbiol. 2011; 2:105. PMC: 3119406. DOI: 10.3389/fmicb.2011.00105. View

Gold B, Nathan C . Targeting Phenotypically Tolerant Mycobacterium tuberculosis. Microbiol Spectr. 2017; 5(1). PMC: 5367488. DOI: 10.1128/microbiolspec.TBTB2-0031-2016. View

Lupoli T, Fay A, Adura C, Glickman M, Nathan C . Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK. Proc Natl Acad Sci U S A. 2016; 113(49):E7947-E7956. PMC: 5150378. DOI: 10.1073/pnas.1617644113. View

Kohanski M, Dwyer D, Hayete B, Lawrence C, Collins J . A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007; 130(5):797-810. DOI: 10.1016/j.cell.2007.06.049. View

Sassetti C, Boyd D, Rubin E . Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003; 48(1):77-84. DOI: 10.1046/j.1365-2958.2003.03425.x. View

Cehovin A, Coates A, Hu Y, Riffo-Vasquez Y, Tormay P, Botanch C . Comparison of the moonlighting actions of the two highly homologous chaperonin 60 proteins of Mycobacterium tuberculosis. Infect Immun. 2010; 78(7):3196-206. PMC: 2897374. DOI: 10.1128/IAI.01379-09. View

Abdeen S, Salim N, Mammadova N, Summers C, Frankson R, Ambrose A . GroEL/ES inhibitors as potential antibiotics. Bioorg Med Chem Lett. 2016; 26(13):3127-3134. DOI: 10.1016/j.bmcl.2016.04.089. View

Rodriguez G, Voskuil M, Gold B, Schoolnik G, Smith I . ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect Immun. 2002; 70(7):3371-81. PMC: 128082. DOI: 10.1128/IAI.70.7.3371-3381.2002. View

10.

Hartl F, Bracher A, Hayer-Hartl M . Molecular chaperones in protein folding and proteostasis. Nature. 2011; 475(7356):324-32. DOI: 10.1038/nature10317. View

11.

Russo F, Gising J, Akerbladh L, Roos A, Naworyta A, Mowbray S . Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents. ChemistryOpen. 2015; 4(3):342-62. PMC: 4522185. DOI: 10.1002/open.201500001. View

12.

Deuerling E, Tomoyasu T, Mogk A, Bukau B . Trigger factor and DnaK cooperate in folding of newly synthesized proteins. Nature. 1999; 400(6745):693-6. DOI: 10.1038/23301. View

13.

Fay A, Glickman M . An essential nonredundant role for mycobacterial DnaK in native protein folding. PLoS Genet. 2014; 10(7):e1004516. PMC: 4109909. DOI: 10.1371/journal.pgen.1004516. View

14.

Feng X, Zhu W, Schurig-Briccio L, Lindert S, Shoen C, Hitchings R . Antiinfectives targeting enzymes and the proton motive force. Proc Natl Acad Sci U S A. 2015; 112(51):E7073-82. PMC: 4697371. DOI: 10.1073/pnas.1521988112. View

15.

Chapman E, Farr G, Usaite R, Furtak K, Fenton W, Chaudhuri T . Global aggregation of newly translated proteins in an Escherichia coli strain deficient of the chaperonin GroEL. Proc Natl Acad Sci U S A. 2006; 103(43):15800-5. PMC: 1613232. DOI: 10.1073/pnas.0607534103. View

16.

Chesnokova L, Slepenkov S, Witt S . The insect antimicrobial peptide, L-pyrrhocoricin, binds to and stimulates the ATPase activity of both wild-type and lidless DnaK. FEBS Lett. 2004; 565(1-3):65-9. DOI: 10.1016/j.febslet.2004.03.075. View

17.

Dillon N, Peterson N, Rosen B, Baughn A . Pantothenate and pantetheine antagonize the antitubercular activity of pyrazinamide. Antimicrob Agents Chemother. 2014; 58(12):7258-63. PMC: 4249577. DOI: 10.1128/AAC.04028-14. View

18.

Lillebaek T, Dirksen A, Baess I, Strunge B, Thomsen V, Andersen A . Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. J Infect Dis. 2002; 185(3):401-4. DOI: 10.1086/338342. View

19.

Porankiewicz J, Wang J, Clarke A . New insights into the ATP-dependent Clp protease: Escherichia coli and beyond. Mol Microbiol. 1999; 32(3):449-58. DOI: 10.1046/j.1365-2958.1999.01357.x. View

20.

MacMicking J, Taylor G, McKinney J . Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science. 2003; 302(5645):654-9. DOI: 10.1126/science.1088063. View