The Role of ClpP Protease in Bacterial Pathogenesis and Human Diseases

Bhandari, Vaibhav; Wong, Keith S.; Zhou, Jin; Mabanglo, Mark; Batey, Robert A.; Houry, Walid

doi:10.1021/acschembio.8b00124

Cited by 121 publications

(148 citation statements)

References 103 publications

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“…In all these cases, the ClpP protease seems to have a central role in protein homeostasis. Dysfunction of the system can lead to severe developmental defects, reduction in the pathogenicity, or lethal (21,36,37). The current finding is additional evidence to support that T6SS can manipulate the essential and highly conserved molecules of recipient cells to achieve better inhibiting performance (38).…”

Section: Discussionsupporting

confidence: 52%

See 1 more Smart Citation

Identification ofEscherichia coliClpAP in regulating susceptibility to type VI secretion system-mediated attack byAgrobacterium tumefaciens

Lin

Sriramoju

et al. 2019

Preprint

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Type VI secretion system (T6SS) is an effector delivery system used by gram-negative bacteria to kill other bacteria or eukaryotic host to gain fitness. In Agrobacterium tumefaciens, T6SS has been shown to kill other bacteria such as Escherichia coli. Interestingly, the A. tumefaciens T6SS killing efficiency differs when using different E. coli strains as recipient cells. Thus, we hypothesize that a successful T6SS killing not only relies on attacker T6SS activity but also depends on recipient factors. A high-throughput interbacterial competition assay was employed to test the hypothesis by screening for mutants with reduced killing outcomes caused by A. tumefaciens strain C58. From the 3909 E. coli Keio mutants screened, 16 candidate mutants were filtered out. One strain, ΔclpP::Kan, showed ten times more resistant to T6SS-mediating killing but restored its susceptibility when complemented with clpP in trans. ClpP is a universal and highly conserved protease that exists in both prokaryotes and eukaryotic organelles. In E. coli, ClpP uses either ClpA or ClpX as an adaptor for substrate specificity. Therefore, the susceptibility of the ΔclpA::Kan and ΔclpX::Kan was also tested. The T6SS attack

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Section: Discussionsupporting

confidence: 52%

“…3). The ClpP complex is a well-studied, house-keeping AAA + serine protease in E. coli (20)(21)(22). A functional ClpP complex consists of a tetradodecameric ClpP and its associated AAA + ATPase substrate recognizing partner ClpA or ClpX, both in a hexameric form (19).…”

Section: The Clpp Protein But Not Its Protease Activity Plays a Critimentioning

confidence: 99%

Identification ofEscherichia coliClpAP in regulating susceptibility to type VI secretion system-mediated attack byAgrobacterium tumefaciens

Lin

Sriramoju

et al. 2019

Preprint

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“…Z-LY-CMK (DB07571) is a covalent inhibitor of the ATP-dependent Clp protease proteolytic subunit (ClpP) 55 . Interestingly, the ClpP enzyme has recently gained attention as a promising drug target for antibiotics development 56 . If con rmed, the possibility of this compound to act both as an antimicrobial agent and SARS-CoV-2 inhibitor would be particularly useful to treat secondary bacterial infections, potentially affecting COVID-19 patients.…”

Section: Candidates To Drug Repurposing With Bene Cial Polypharmacologymentioning

confidence: 99%

Drug repurposing and polypharmacology to fight SARS-CoV-2 through the inhibition of the main protease

Pinzi

Tinivella

Caporuscio

et al. 2020

Preprint

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There is an urgent need to develop therapeutic options to fight the outbreak of a novel Coronavirus (SARS-CoV-2), which causes a disease named COVID-19 and is spreading rapidly around the world. Drug repurposing can significantly accelerate the identification of drug candidates suitable for clinical evaluation. Moreover, drugs with polypharmacological effects may increase antiviral activity and/or counteract severe disease complications concurrently affecting COVID-19 patients. Herein, we present the results of a computational drug repurposing campaign in search for potential inhibitors of the main protease of SARS-CoV-2. To this aim, the complete DrugBank database, including drug metabolites, was docked to the recently solved crystal structure of the SARS-CoV-2 Mpro and the results were post-processed by using our in-house tool BEAR. Here we report 32 promising drugs that could be repositioned to fight SARS-CoV-2. Some of them have already entered clinical trials against COVID-19, thus supporting our results, but the vast majority of the selected compounds is new and has never been considered before. For each repurposed compound its therapeutic relevance and the potential beneficial polypharmacological effects that may arise thanks to its original therapeutic indication are thoroughly discussed.

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“…Caseinolytic protease ClpP, a widely conserved self-compartmentalizing serine protease in bacteria, plays essential roles in protein metabolism and regulates diverse physiological functions including cell motility, genetic competence, cell differentiation, sporulation, and virulence, and is thus an attractive target for antibiotic development [1][2][3][4][5][6][7][8]. Notably, ClpP is an novel drug target for which both inhibition and activation result in an attenuated or lethal phenotype in many pathogens; thus agonists and antagonists Inhibiting ClpP1P2 by addressing the equatorial handle domain of ClpP1…”

Section: Introductionmentioning

confidence: 99%

Inhibiting Mycobacterium tuberculosis ClpP1P2 by addressing the equatorial handle domain of ClpP1 subunit

Yang

Zhu

et al. 2019

Preprint

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19Unlike other bacterial ClpP systems, mycobacterial ClpP1P2 complex is essential 20 for mycobacterial survival. The functional details of Mycobacterium tuberculosis (Mtb) 21 ClpP1P2 remains largely elusive and selectively targeting ClpP of different species is a 22 big challenge. In this work, cediranib was demonstrated to significantly decrease the 23 activity of MtbClpP1P2. By solving the crystal structure of cediranib-bound 24 MtbClpP1P2, we found that cediranib dysregulates MtbClpP1P2 by interfering with 25 handle domain of the equatorial region of MtbClpP1, indicating that the inter-ring 26 dynamics are crucial for its function. This finding provides direct evidence for the 27 notion that a conformational switch in the equatorial handle domain is essential for ClpP 28 activity. We also present biochemical data to interpret the distinct interaction pattern 29 and inhibitory properties of cediranib toward MtbClpP1P2. These results suggest that 30 the variable handle domain region is responsible for the species-selectivity of cediranib, 31 which suggests the equatorial handle domain as a potential region for screening 32 pathogen-specific ClpP inhibitors. 33 Introduction 34 Caseinolytic protease ClpP, a widely conserved self-compartmentalizing serine 35 protease in bacteria, plays essential roles in protein metabolism and regulates diverse 36 physiological functions including cell motility, genetic competence, cell differentiation, 37 sporulation, and virulence, and is thus an attractive target for antibiotic development[1-38 8]. Notably, ClpP is an novel drug target for which both inhibition and activation result 39 in an attenuated or lethal phenotype in many pathogens; thus agonists and antagonists 40 Inhibiting ClpP1P2 by addressing the equatorial handle domain of ClpP1 3 / 42 aimed at the ClpP system represent promising drug candidates for further evaluation[9, 41 10]. The ClpP enzyme of Mycobacterium tuberculosis (MTB), MtbClpP1P2, exerts its 42 proteolytic function by a heterotetramer of two protein subunits, ClpP1 and ClpP2[11, 43 12]. Moreover, encoding genes of subunits ClpP1 and ClpP2, have been shown to be 44 essential genes for MTB survival and the deletion of either gene causes bacterial 45 death[13]. A panel of MtbClpP1P2 inhibitors have been reported and they can be 46 classified into two categories depending on their action modes. The first kind of small 47 molecules act on the catalytically active center, covalently modifying the serine 48 residues of the active sites of two subunits of MtbClpP1P2, including bortezomib, 49 boron-containing analogues and beta lactones[14-17]. The second kind of inhibitors act 50 on the chaperone protein (ClpX/ClpC1) binding site that competitively binds to the 51 surface of the ClpP2 subunit. Representative molecules of this category are ADEP and 52 its analogs[12]. Since the chaperones binding L/IGF region of ClpP2 subunit is highly 53 conserved, as with the inhibitor of the MtbClpP1P2 catalytic center[18], the ADEP 54 compounds are nonse...

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The Role of ClpP Protease in Bacterial Pathogenesis and Human Diseases

Cited by 121 publications

References 103 publications

Identification ofEscherichia coliClpAP in regulating susceptibility to type VI secretion system-mediated attack byAgrobacterium tumefaciens

Identification ofEscherichia coliClpAP in regulating susceptibility to type VI secretion system-mediated attack byAgrobacterium tumefaciens

Drug repurposing and polypharmacology to fight SARS-CoV-2 through the inhibition of the main protease

Inhibiting Mycobacterium tuberculosis ClpP1P2 by addressing the equatorial handle domain of ClpP1 subunit

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