Targeting the Proteostasis Network for Mycobacterial Drug Discovery

Lupoli, Tania J.; Vaubourgeix, Julien; Burns-Huang, Kristin; Gold, Ben

doi:10.1021/acsinfecdis.7b00231

Cited by 62 publications

(67 citation statements)

References 238 publications

(551 reference statements)

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“…Proper protein homeostasis is a vital aspect of bacterial growth and, in some cases, of bacterial virulence (Lupoli et al, 2018;Culp & Wright, 2017). Of the bacterial proteasome complexes, Clp is the most validated therapeutic target (Raju et al, 2012;Lee & Suh, 2016;Zhou et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Several macrocyclic peptides that specifically interact with ClpC1 have been identified to disrupt the normal functioning of the proteasome (Lupoli et al, 2018). Cyclomarin A (CYMA) is structurally similar to the heptapeptide rufomycin I (RUF-I), while ohmyungsamycin A (OMS-A) and ohmyungsamycin B (OMS-B) are structurally similar to ecumicin (ECU) (Um et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions

Wolf

Lee

Zagal

et al. 2020

Acta Crystallogr D Struct Biol

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The biological processes related to protein homeostasis in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, have recently been established as critical pathways for therapeutic intervention. Proteins of particular interest are ClpC1 and the ClpC1-ClpP1-ClpP2 proteasome complex. The structure of the potent antituberculosis macrocyclic depsipeptide ecumicin complexed with the N-terminal domain of ClpC1 (ClpC1-NTD) is presented here. Crystals of the ClpC1-NTD-ecumicin complex were monoclinic (unit-cell parameters a = 80.0, b = 130.0, c = 112.0 Å , = 90.07 ; space group P2 1 ; 12 complexes per asymmetric unit) and diffracted to 2.5 Å resolution. The structure was solved by molecular replacement using the self-rotation function to resolve space-group ambiguities. The new structure of the ecumicin complex showed a unique 1:2 (target:ligand) stoichiometry exploiting the intramolecular dyad in the -helical fold of the target N-terminal domain. The structure of the ecumicin complex unveiled extensive interactions in the uniquely extended N-terminus, a critical binding site for the known cyclopeptide complexes. This structure, in comparison with the previously reported rufomycin I complex, revealed unique features that could be relevant for understanding the mechanism of action of these potential antituberculosis drug leads. Comparison of the ecumicin complex and the ClpC1-NTD-L92S/L96P double-mutant structure with the available structures of rufomycin I and cyclomarin A complexes revealed a range of conformational changes available to this small N-terminal helical domain and the minor helical alterations involved in the antibiotic-resistance mechanism. The different modes of binding and structural alterations could be related to distinct modes of action. research papers Acta Cryst. (2020). D76, 458-471 Wolf et al. ClpC1-NTD in complex with ecumicin 459

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions

Wolf

Lee

Zagal

et al. 2020

Acta Crystallogr D Struct Biol

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“…HtpG and DnaK are essential for cell growth, native protein folding and immune response. Several studies suggested DnaK and HtpG as potential drug target [26] [27].…”

Section: Resultsmentioning

confidence: 99%

Designing of Short Interfering RNAS (siRNAs) for Tuberculosis

Verma¹,

Negi²,

Pant*³

et al. 2020

IJITEE

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The control of Tuberculosis is an obstacle that many researchers have been trying to overcome from several decades, as it remains the cause of millions of deaths per year. Though there are several drugs available but due to drug resistance, there is an extensive need of new and effective ways of treatment. Computational study was performed to design siRNA for the genes atpG, dnaK and htpG as all these genes are important for the survival of bacterium Mycobacterium tuberculosis. Multiple sequence alignment was done using Mega X software on the coding sequences (cds) of studied Mtb strains, which were retrieved from the NCBI database. The i-score designer was used for designing of potent siRNA. The SMEpred webserver was used to validate the data collected from the i-score designer, which was further used to calculate the efficacy as well as to predict the chemically modified siRNA (cm-siRNA). Results show that the studied genes were conserved in all the studied strains. MFE was calculated using RNAfold server and sequences with the lowest MFE was selected, as they are proved to have higher stability. This result can be used to develop novel therapeutic applications

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“…In Mtb, proteostasis network provides protection from different stresses and host immunity. The machinery used for this comprises a complex network of chaperones, proteases, and a eukaryotic-like proteasome (functionally linked AAA -ATPases domain protein family) which helps in evading the host immunity by maintaining the integrity of the mycobacterial proteome 44 . Besides this, AAA -ATPases domain protein family also play a significant role in recognition of ESAT-6 secretion system (ESX-1) secreted virulence factors 45 , which is a type VII secretion system of Mtb and is capable to form pores and rupture phagosomes 46 .…”

Section: Discussionmentioning

confidence: 99%

Comparative in-silico proteomic analysis discerns potential granuloma proteins of Yersinia pseudotuberculosis

Aswal

Garg

Singhal

et al. 2020

Sci Rep

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Yersinia pseudotuberculosis is one of the three pathogenic species of the genus Yersinia. Most studies regarding pathogenesis of Y. pseudotuberculosis are based on the proteins related to type iii secretion system, which is a well-known primary virulence factor in pathogenic Gram-negative bacteria, including Y. pseudotuberculosis. information related to the factors involved in Y. pseudotuberculosis granuloma formation is scarce. in the present study we have used a computational approach to identify proteins that might be potentially involved in formation of Y. pseudotuberculosis granuloma. A comparative proteome analysis and conserved orthologous protein identification was performed between two different genera of bacteria-Mycobacterium and Yersinia, their only common pathogenic trait being ability to form necrotizing granuloma. comprehensive analysis of orthologous proteins was performed in proteomes of seven bacterial species. this included M. tuberculosis, M. bovis and M. avium paratuberculosis-the known granuloma forming Mycobacterium species, Y. pestis and Y. frederiksenii-the non-granuloma forming Yersinia species and, Y. enterocolitica-that forms micro-granuloma and, Y. pseudotuberculosis-a prominent granuloma forming Yersinia species. In silico proteome analysis indicated that seven proteins (UniProt id A0A0U1QT64, A0A0U1QTE0, A0A0U1QWK3, A0A0U1R1R0, A0A0U1R1Z2, A0A0U1R2S7, A7FMD4) might play some role in Y. pseudotuberculosis granuloma. Validation of the probable involvement of the seven proposed Y. pseudotuberculosis granuloma proteins was done using transcriptome data analysis and, by mapping on a composite protein-protein interaction map of experimentally proved M. tuberculosis granuloma proteins (RD1 locus proteins, ESAT-6 secretion system proteins and intra-macrophage secreted proteins). Though, additional experiments involving knocking out of each of these seven proteins are required to confirm their role in Y. pseudotuberculosis granuloma our study can serve as a basis for further studies on Y. pseudotuberculosis granuloma. The genus Yersinia is comprised of Gram-negative, catalase-positive, facultative anaerobic enteric-bacteria. Though, the optimal temperature for growth is 28 °C, some members of the genus can survive at low temperatures ca. 4 °C 1. Most species of the genus Yersinia grow extracellularly, except Y. pseudotuberculosis and Y. pestis which are capable of intracellular growth, i.e. inside the host macrophages 2. Of the sixteen known species of Yersinia, only three are pathogenic Y. pestis, Y. pseudotuberculosis and Y. enterocolitica 3,4. In humans, infection with Y. pestis results in plague, while infection with Y. pseudotuberculosis and Y. enterocolitica results in gastroenteritis, which is usually self-limiting 5. Besides man, Y. pseudotuberculosis can infect a wide range of animals including swines, dogs, rodents, birds etc. 6-9. Y. pseudotuberculosis infection in animals can lead to tuberculosis-like symptoms, including localized tissue necrosis and granulomas in the liver, sple...

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Targeting the Proteostasis Network for Mycobacterial Drug Discovery

Cited by 62 publications

References 238 publications

Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions

Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions

Designing of Short Interfering RNAS (siRNAs) for Tuberculosis

Comparative in-silico proteomic analysis discerns potential granuloma proteins of Yersinia pseudotuberculosis

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