Lead compounds and key residues of ribosomal protein S1 in drug-resistant Mycobacterium tuberculosis

Zhi, Yunbao; Dai, Yazhuang; Yang, Juanjuan; Tan, Suxu; Lin, Donghai; Lin, Kejiang

doi:10.1016/j.bioorg.2018.09.024

Cited by 13 publications

(20 citation statements)

References 28 publications

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“…It is known that the ribosomal S1 protein can be used as a target for the development of antibiotics against the bacterium Mycobacterium tuberculosis , the causative agent of tuberculosis [ 65 , 66 ]. In turn, the present study identified amyloidogenic sequences of the S1 protein from P. aeruginosa that can be used to create antimicrobial peptides capable of targeting antibiotic-resistant strains of this pathogen.…”

Section: Discussionmentioning

confidence: 99%

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Grishin

Dzhus

Glukhov

et al. 2021

IJMS

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Bacterial S1 protein is a functionally important ribosomal protein. It is a part of the 30S ribosomal subunit and is also able to interact with mRNA and tmRNA. An important feature of the S1 protein family is a strong tendency towards aggregation. To study the amyloidogenic properties of S1, we isolated and purified the recombinant ribosomal S1 protein of Pseudomonas aeruginosa. Using the FoldAmyloid, Waltz, Pasta 2.0, and AGGRESCAN programs, amyloidogenic regions of the protein were predicted, which play a key role in its aggregation. The method of limited proteolysis in combination with high performance liquid chromatography and mass spectrometric analysis of the products, made it possible to identify regions of the S1 protein from P. aeruginosa that are protected from the action of proteinase K, trypsin, and chymotrypsin. Sequences of theoretically predicted and experimentally identified amyloidogenic regions were used to synthesize four peptides, three of which demonstrated the ability to form amyloid-like fibrils, as shown by electron microscopy and fluorescence spectroscopy. The identified amyloidogenic sites can further serve as a basis for the development of new antibacterial peptides against the pathogenic microorganism P. aeruginosa.

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Section: Discussionmentioning

confidence: 99%

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Grishin

Dzhus

Glukhov

et al. 2021

IJMS

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“…In recent years, ligand‐based virtual screening methods have gradually been applied in the discovery of ribosome targeting agents. Zhi et al 127 used pyrazinamide, a prodrug of a small molecule inhibitor of the ribosomal S1 protein, and its in vivo active form pyrazinoic acid as templates for virtual screening from multiple databases. On the basis of aspects such as molecular weight, aromatic characteristics, spatial and electrostatic similarity, and fingerprint similarity, combined with subsequent docking calculations, a total of 21 small molecules were screened out and synthesized for further in vitro antibacterial activity and protein binding tests.…”

Section: Challenges and Advances In Ribosomal Antibiotics And Bacterial Ribosomesmentioning

confidence: 99%

“…In addition, compounds 9 , 11 , and 14 can completely inhibit the growth of pyrazinamide‐resistant M. tuberculosis at a concentration of 256 µg/ml, while the pyrazinamide cannot inhibit the growth of the strain at the same concentration. This study laid the foundation for the discovery of new chemicals against pyrazinamide‐resistant M. tuberculosis and the development of specific inhibitors of ribosomal S1 protein 127 . Tam et al 128 also used a ligand‐based screening strategy in the discovery of M. tuberculosis inhibitors (Figure 12B).…”

Section: Challenges and Advances In Ribosomal Antibiotics And Bacterial Ribosomesmentioning

confidence: 99%

“…However, the compromise would reduce the accuracy of docking study and simulation. The ligand‐based drug discovery methods 127–130 and machine learning 128 have well fixed the ribosomal complexity problem, which could be alternative strategies in the virtual discovery of ribosome‐targeting antibacterial agents. Of course, with the development of computing science and quantum computer, we believe the molecular dynamics simulation with full‐length ribosomes may be high efficiency and energy saving, and importantly, more accurate.…”

Section: Opportunities and Perspectivementioning

confidence: 99%

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Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

Zhang

Bai

et al. 2021

Medicinal Research Reviews

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Ribosomes, which synthesize proteins, are critical organelles for the survival and growth of bacteria. About 60% of approved antibiotics discovered so far combat pathogenic bacteria by targeting ribosomes. However, several issues, such as drug resistance and toxicity, have impeded the clinical use of ribosome‐targeting antibiotics. Moreover, the complexity of the bacteria ribosome structure has retarded the discovery of new ribosome‐targeting agents that are considered as the key to the drug‐resistance and toxicity. To deal with these challenges, efforts such as medicinal chemistry optimization, combination treatment, and new drug delivery system have been developed. But not enough, the development of structural biology and new screening methods bring powerful tools, such as cryo‐electron microscopy technology, advanced computer‐aided drug design, and cell‐free in vitro transcription/translation systems, for the discovery of novel ribosome‐targeting antibiotics. Thus, in this paper, we overview the research on different aspects of bacterial ribosomes, especially focus on discussing the challenges in the discovery of ribosome‐targeting antibacterial drugs and advances made to address issues such as drug‐resistance and selectivity, which, we believe, provide perspectives for the discovery of novel antibiotics.

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“…PZA is a prodrug, activated by MTB encoded pncA into POA, targeting RpsA. POA-resistance may occur when mutations arise at the C-terminus of RpsA (MtRpsA CTD ), causing conformational changes (Yang et al, 2015;Huang et al, 2019;Khan et al, 2019a;Shi et al, 2019;Singh et al, 2019;Zhi et al, 2019). Residues in the fourth S1 domain, which is known as a highly conserved region, were able to interact with POA (Shi et al, 2011;Yang et al, 2015).…”

Section: Mutants Selection In Rpsamentioning

confidence: 99%

Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance

Khan

Ali

Zeb³

et al. 2020

Front. Mol. Biosci.

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A central approach for better understanding the forces involved in maintaining protein structures is to investigate the protein folding and thermodynamic properties. The effect of the folding process is often disturbed in mutated states. To explore the dynamic properties behind mutations, molecular dynamic (MD) simulations have been widely performed, especially in unveiling the mechanism of drug failure behind mutation. When comparing wild type (WT) and mutants (MTs), the structural changes along with solvation free energy (SFE), and Gibbs free energy (GFE) are calculated after the MD simulation, to measure the effect of mutations on protein structure. Pyrazinamide (PZA) is one of the first-line drugs, effective against latent Mycobacterium tuberculosis isolates, affecting the global TB control program 2030. Resistance to this drug emerges due to mutations in pncA and rpsA genes, encoding pyrazinamidase (PZase) and ribosomal protein S1 (RpsA) respectively. The question of how the GFE may be a measure of PZase and RpsA stabilities, has been addressed in the current review. The GFE and SFE of MTs have been compared with WT, which were already found to be PZA-resistant. WT structures attained a more stable state in comparison with MTs. The physiological effect of a mutation in PZase and RpsA may be due to the difference in energies. This difference between WT and MTs, depicted through GFE plots, might be useful in predicting the stability and PZA-resistance behind mutation. This study provides useful information for better management of drug resistance, to control the global TB problem.

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Lead compounds and key residues of ribosomal protein S1 in drug-resistant Mycobacterium tuberculosis

Cited by 13 publications

References 28 publications

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Identification of Amyloidogenic Regions in Pseudomonas aeruginosa Ribosomal S1 Protein

Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance

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