ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets
Abstract
:1. Introduction
2. Caseinolytic Proteins: Classification, Function and Structure
2.1. Catalytic Subunit—ClpP
2.2. Regulatory Subunits—Clp ATPases
3. Caseinolytic Proteins Targeted in ESKAPE Pathogens
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Resistance Strategy | Resistance Mechanism | Antibiotics | ESKAPE Pathogens | References |
---|---|---|---|---|
Drug inactivation | Production of β-lactamase enzyme, which hydrolyses β-lactam rings | β-lactam (penicillin, carbapenems and | K. pneumoniae | [1,3,22] |
cephalosporins) | P. aeruginosa, Enterobacter | |||
Contains chromosomally encoded AAC(6′)-Ii, which is responsible for enzymatic inactivation and EfmM ribosomal methylation | Tobramycin | E. faecium | [23] | |
Carbapenemases, metallo-β-lactamases 2 and oxacillinase serine β-lactamases produced to catalyse antibiotic hydrolysis | Colistin, imipenem | A. baumannii | [3] | |
Decreased drug influx | Reduce the amount of porin protein OprD, or via loss of an outer membrane protein (Omp) | β-lactam (Imipenem and meropenem) | P. aeruginosa, A. baumannii | [3,23] |
Expresses enterococcal surface protein (ESP), which results in the formation of thicker biofilms | Vancomycin | E. faecium | [1] | |
Thick cell wall traps and reduces antibiotic permeation | Vancomycin | S. aureus | [1] | |
Mutation of mbrB gene | Colistin | K. pneumoniae | [24] | |
Outer membrane (OmpF) protein with exclusion limit | MDR 1 | P. aeruginosa | [1] | |
Developing 4 resistant nodulation division (RND) type MDR efflux pump to remove toxic compounds from the periplasm and cytoplasm | MDR 1 | P. aeruginosa | [3] | |
Efflux pump system | Nor-like efflux pump | Hydrophilic fluoroquinolones | E. faecium | [23] |
Expression of Penicillin-binding proteins (PBPs) | β-lactam (Penicillin, Cephalosporins, Carbapenems) | S. aureus | [1,3] | |
Cephalosporins and aminoglycosides | E. faecium | [23] | ||
Upregulation of MexAB-OprM | Sulfonamides, cephalosporins, β-lactams, fluoroquinolones | P. aeruginosa | [1] | |
AcrAB-TolC | Tetracyclines (including tigecycline) | K. pneumoniae | [25] | |
Alteration of terminal sequence of cell wall precursors | VanA | E. faecium | [1] | |
Drug site modification | Expresses mecA, which encodes a low-affinity penicillin-binding protein | β-lactam (Penicillin, Methicillin) | S. aureus | [1] |
Expression of Aminoglycoside-modifying enzymes | Aminoglycosides | P. aeruginosa | [26] | |
Qnr acts as a DNA homologue to compete for the DNA-binding site of DNA gyrase and topoisomerase IV | Quinolone | K. pneumoniae | [25] |
Clp Catalytic Subunit | |||
---|---|---|---|
Species | Functions | References | |
ClpP | A number of bacteria including Escherichia coli, Bacillus subtilis, S. aureus | Proteolysis of damaged or misfolded proteins | [31] |
Clp regulatory subunit 1 | |||
ClpA 2 | Gram-positive Proteobacteria | Protein quality control | [32] |
ClpB | Prokaryotes, yeast, and plants | Disaggregation of stress-damaged proteins | [33,34,35] |
Porphyromonas gingivalis | Intracellular replication and survival | [36] | |
ClpC | Gram-positive bacteria (Firmicutes and Actinobacteria) and Cyanobacteria | Protein quality control, red blood cell lysis, regulate expression of virulence factors | [32,37] |
ClpD | Chloroplasts of higher plants | Molecular chaperone | [35] |
ClpE | Firmicutes | Thermotolerance, cell division and virulence | [32] |
ClpK | K. pneumonia | Thermotolerance | [38] |
ClpL | Streptococcus pneumoniae | Nucleotide phosphohydrolase activity, stabilises unfolded proteins, prevents protein aggregation | [39] |
ClpV | Gram-negative bacteria | Component of the type V1 secrection system | [40] |
ClpM | Mus musculus | Protein quality control | [35,41] |
ClpN | Pseudomonas aeruginosa | Cell division | [35,41] |
ClpX | Proteobacteria, Firmicutes and Thermatogae | Protein quality control, cell division, heat tolerance and virulence | [32,36] |
ClpY | Gram-positive Proteobacteria | Cell division, heat shock response and capsule transcription | [32] |
ESKAPE Pathogens | Caseinolytic Proteins | References |
---|---|---|
E. faecium | ClpP | [64,65] |
ClpC | [64,66] | |
S. aureus | ClpP, ClpB, ClpC | [36,63] |
ClpX | [36,63] | |
K. pneumoniae | ClpK | [16,38,67] |
A. baumannii | ClpP | [68,69] |
P. aeruginosa | ClpXP and ClpP2 | [48,70] |
ClpP | [38] | |
ClpG | [71] | |
Enterobacter | None reported |
Compound | Structure 1 | Mechanism of Action | References |
---|---|---|---|
334 | Deoligomerization of S. aureus ClpX, disrupts the ClpXP complex and blocks ClpX ATPase activity. S. aureus produces lower levels of toxins, such as hemolysins in the presence of the compound. | [43,74] | |
D3 | Irreversibly inhibits ClpP in methicillin-resistant S. aureus. Most potent inhibitor. | [43] | |
E2 | Irreversibly inhibits ClpP in methicillin-resistant S. aureus | [43] | |
G2 | Irreversibly inhibits ClpP in methicillin-resistant S. aureus | [43] | |
Acyldepsipeptides (ADEPs) | Prevents complex formation between ClpP and Clp ATPases in Gram-positive bacteria, such as Enterococci and S. aureus | [43,72,73] | |
Ecumicin | Binds to the N-terminal domain of ClpC1 of M. tuberculosis. Stimulates the ATPase hydrolysis activity of M. tuberculosis ClpC1 and at the same time decouples ClpC1 and ClpP, therefore inhibiting proteolytic activity and resulting in cell death. | [43,75] | |
Cyclomarin A | Binds to the N-terminal domain of ClpC1 of M. tuberculosis and prevents the movement of the N-terminal domain. Causes excessive proteolysis. | [43,76,77] | |
Lassomycin | Binds to an acidic N-terminal pocket on ClpC1. Stimulates ATPase activity of ClpC1 from M. tuberculosis, however it also inhibits ATP-dependent degradation of proteins. Uncouples ClpC1 from ClpP1 and ClpP2, resulting in the death of the cell as unnecessary proteins build up. | [16,76] | |
Rufomycin | Interacts with the N-terminal domain of ClpC1 of M. tuberculosis. Decreases the proteolytic activity of the ClpC1 and ClpP complex, therefore resulting in the build-up of proteins in the cell. | [77] | |
Armeiaspirols | Inhibits ClpXP and ClpYQ in Bacillus subtilis by binding to the ATPase domains and therefore inhibits the function of the complexes. Inhibits ATP hydrolysis and proteolysis. | [78] | |
Hydantoin analog | Inhibits the ClpXP complex. Binds to a binding pocket on ClpP and impairs complex substrate turnover. | [79] |
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Motiwala, T.; Mthethwa, Q.; Achilonu, I.; Khoza, T. ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets. Antibiotics 2022, 11, 1218. https://doi.org/10.3390/antibiotics11091218
Motiwala T, Mthethwa Q, Achilonu I, Khoza T. ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets. Antibiotics. 2022; 11(9):1218. https://doi.org/10.3390/antibiotics11091218
Chicago/Turabian StyleMotiwala, Tehrim, Qiniso Mthethwa, Ikechukwu Achilonu, and Thandeka Khoza. 2022. "ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets" Antibiotics 11, no. 9: 1218. https://doi.org/10.3390/antibiotics11091218