An antipathogenic compound that targets the OxyR peroxide sensor in Open Access

Abstract

Antipathogenic or antivirulence strategy is to target a virulence pathway that is dispensable for growth, in the hope to mitigate the selection for drug resistance.

Peroxide stress responses are one of the conserved virulence pathways in bacterial pathogens and thus good targets for antipathogenic strategy.

This study aims to identify a new chemical compound that targets OxyR, the peroxide sensor required for the full virulence of the opportunistic human pathogen, .

Computer-based virtual screening under consideration of the ‘eNTRy’ rules and molecular docking were conducted on the reduced form of the OxyR regulatory domain (RD). Selected hits were validated by their ability to phenocopy the null mutant and modulate the redox cycle of OxyR.

We first isolated three robust chemical hits that inhibit OxyR without affecting prototrophic growth or viability. One (compound 1) of those affected the redox cycle of OxyR in response to HO treatment, in a way to impair its function. Compound 1 displayed selective antibacterial efficacy against in infection model, without antibacterial activity against .

These results suggest that compound 1 could be an antipathogenic hit inhibiting the OxyR. More importantly, our study provides an insight into the computer-based discovery of new-paradigm selective antibacterials to treat Gram-negative bacterial infections presumably with few concerns of drug resistance.

Funding
This study was supported by the:
  • National Research Foundation of Korea (Award NRF-2017M3A9E4077205)
    • Principle Award Recipient: You-HeeCho
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.001341
2021-04-08
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jmm/70/4/jmm001341.html?itemId=/content/journal/jmm/10.1099/jmm.0.001341&mimeType=html&fmt=ahah

References

  1. Bassetti M, Peghin M, Vena A, Giacobbe DR. Treatment of infections due to MDR Gram-negative bacteria. Front Med 2019; 6:74 [View Article]
    [Google Scholar]
  2. Founou RC, Founou LL, Essack SY. Clinical and economic impact of antibiotic resistance in developing countries: a systematic review and meta-analysis. PLoS One 2017; 12:e0189621 [View Article][PubMed]
    [Google Scholar]
  3. Dickey SW, Cheung GYC, Otto M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat Rev Drug Discov 2017; 16:457–471 [View Article][PubMed]
    [Google Scholar]
  4. Tommasi R, Brown DG, Walkup GK, Manchester JI, Miller AA. ESKAPEing the labyrinth of antibacterial discovery. Nat Rev Drug Discov 2015; 14:529–542 [View Article][PubMed]
    [Google Scholar]
  5. Kalia VC, Patel SK, Kang YC, Lee J-K. Quorum sensing inhibitors as antipathogens: biotechnological applications. Biotechnol Adv 2019; 37:68–90 [View Article][PubMed]
    [Google Scholar]
  6. Muller S, Feldman MF, Cornelis GR. The type III secretion system of gram-negative bacteria: a potential therapeutic target?. Expert Opin Ther Targets 2001; 5:327–339 [View Article][PubMed]
    [Google Scholar]
  7. Bae H-W, Cho Y-H. Mutational analysis of Pseudomonas aeruginosa OxyR to define the regions required for peroxide resistance and acute virulence. Res Microbiol 2012; 163:55–63 [View Article][PubMed]
    [Google Scholar]
  8. Lau GW, Britigan BE, Hassett DJ. Pseudomonas aeruginosa OxyR is required for full virulence in rodent and insect models of infection and for resistance to human neutrophils. Infect Immun 2005; 73:2550–2553 [View Article][PubMed]
    [Google Scholar]
  9. Wei Q, Minh PNL, Dötsch A, Hildebrand F, Panmanee W et al. Global regulation of gene expression by oxyR in an important human opportunistic pathogen. Nucleic Acids Res 2012; 40:4320–4333 [View Article][PubMed]
    [Google Scholar]
  10. Chung I-Y, Kim B-O, Jang H-J, Cho Y-H. Dual promoters of the major catalase (KatA) govern distinct survival strategies of Pseudomonas aeruginosa . Sci Rep 2016; 6:31185 [View Article][PubMed]
    [Google Scholar]
  11. Heo Y-J, Chung I-Y, Cho W-J, Lee B-Y, Kim J-H et al. The major catalase gene (katA) of Pseudomonas aeruginosa PA14 is under both positive and negative control of the global transactivator oxyR in response to hydrogen peroxide. J Bacteriol 2010; 192:381–390 [View Article][PubMed]
    [Google Scholar]
  12. Kim B-O, Chung I-Y, Cho Y-H. Differential expression of the major catalase, KatA in the two wild type Pseudomonas aeruginosa strains, PAO1 and PA14. J Microbiol 2019; 57:704–710 [View Article][PubMed]
    [Google Scholar]
  13. Kim B-O, Jang H-J, Chung I-Y, Bae H-W, Kim ES et al. Nitrate respiration promotes polymyxin B resistance in Pseudomonas aeruginosa . Antioxid Redox Signal 2021; 34:442-451 [View Article][PubMed]
    [Google Scholar]
  14. Jo I, Chung I-Y, Bae H-W, Kim J-S, Song S et al. Structural details of the oxyR peroxide-sensing mechanism. Proc Natl Acad Sci U S A 2015; 112:6443–6448 [View Article][PubMed]
    [Google Scholar]
  15. Richter MF, Drown BS, Riley AP, Garcia A, Shirai T et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 2017; 545:299–304 [View Article][PubMed]
    [Google Scholar]
  16. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23:3–25 [View Article]
    [Google Scholar]
  17. Lee Y-J, Jang H-J, Chung I-Y, Cho Y-H. Drosophila melanogaster as a polymicrobial infection model for Pseudomonas aeruginosa and Staphylococcus aureus . J Microbiol 2018; 56:534–541 [View Article][PubMed]
    [Google Scholar]
  18. Raftery MJ. Determination of oxidative protein modifications using mass spectrometry. Redox Rep 2014; 19:140–147 [View Article][PubMed]
    [Google Scholar]
  19. Jang H-J, Chung I-Y, Lim C, Chung S, Kim B-O et al. Redirecting an anticancer to an antibacterial hit against methicillin-resistant Staphylococcus aureus . Front Microbiol 2019; 10:350 [View Article][PubMed]
    [Google Scholar]
  20. Mongkolsuk S, Helmann JD. Regulation of inducible peroxide stress responses. Mol Microbiol 2002; 45:9–15 [View Article][PubMed]
    [Google Scholar]
  21. Pinkner JS, Remaut H, Buelens F, Miller E, Aberg V et al. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc Natl Acad Sci U S A 2006; 103:17897–17902 [View Article][PubMed]
    [Google Scholar]
  22. Rooks MG, Veiga P, Reeves AZ, Lavoie S, Yasuda K et al. QseC inhibition as an antivirulence approach for colitis-associated bacteria. Proc Natl Acad Sci U S A 2017; 114:142–147 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.001341
Loading
/content/journal/jmm/10.1099/jmm.0.001341
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed