1887

Abstract

The emergence of resistance to fluconazole in has made the clinical treatment of this microbe difficult. A potential strategy to address this problem involves diminishing fungal resistance to antimicrobial drugs.

Berberine hydrochloride (BH), the primary active ingredient of the traditional Chinese medicine (TCM) Coptis, inhibits the growth of fluconazole-resistant through its action on the high-osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway.

To examine the effect of BH on the HOG-MAPK pathway to assess the potential molecular mechanism by which BH inhibits fluconazole-resistant .

The minimum inhibitory concentration (MIC) of BH to fluconazole-resistant was measured using the broth microdilution approach to determine the concentration of effective drug intervention. Changes in physiological functions regulated by the HOG-MAPK pathway in response to BH treatment were measured, as well as the expression of central signalling pathway genes and key downstream factors by qRT-PCR and Western blotting, respectively.

BH inhibited fluconazole-resistant and the sensitivity to fluconazole increased after BH treatment. At a concentration of 256 and 64 μg ml BH may affect key downstream factors that regulate several physiological functions of by upregulating the core genes expression of , , , and in the HOG-MAPK pathway. Upregulation of , the key gene for glycerol synthesis, increased cell osmotic pressure. BH treatment increased the accumulation of reactive oxygen species by upregulating the expression of the key respiratory metabolism gene and downregulating the expression of the superoxide dismutase gene . Furthermore, downregulation of mycelial-specific hindered the morphological transformation of and inhibition of the chitin synthase gene and the β-(1,3) glucan synthase gene impaired cytoderm integrity.

BH affects multiple target genes in diminishing the resistance of strains to fluconazole. This effect may be related to the action of BH on the HOG-MAPK pathway.

Funding
This study was supported by the:
  • Chengdu University of Traditional Chinese Medicine (Award JSZX2018006)
    • Principle Award Recipient: YanLi
  • Health Department of Sichuan Province (Award 20PJ163)
    • Principle Award Recipient: YanLi
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.001542
2022-06-09
2024-04-25
Loading full text...

Full text loading...

References

  1. Wall G, Montelongo-Jauregui D, Vidal Bonifacio B, Lopez-Ribot JL, Uppuluri P et al. Candida albicans biofilm growth and dispersal: contributions to pathogenesis. Curr Opin Microbiol 2019; 52:1–6 [View Article] [PubMed]
    [Google Scholar]
  2. Liu S, Chen C. Advances in MAPK signaling pathway in pathogenic fungi. Hunan Agricultural Sciences 2017; 11:119–122 [View Article]
    [Google Scholar]
  3. Dunayevich P, Baltanás R, Clemente JA, Couto A, Sapochnik D et al. Heat-stress triggers MAPK crosstalk to turn on the hyperosmotic response pathway. Sci Rep 2018; 8:15168 [View Article] [PubMed]
    [Google Scholar]
  4. Horie T, Tatebayashi K, Yamada R, Saito H et al. Phosphorylated Ssk1 prevents unphosphorylated Ssk1 from activating the Ssk2 mitogen-activated protein kinase kinase kinase in the yeast high-osmolarity glycerol osmoregulatory pathway. Mol Cell Biol 2008; 28:5172–5183 [View Article] [PubMed]
    [Google Scholar]
  5. Cheetham J, Smith DA, da Silva Dantas A, Doris KS, Patterson MJ et al. A single MAPKKK regulates the Hog1 MAPK pathway in the pathogenic fungus Candida albicans. Mol Biol Cell 2007; 18:4603–4614 [View Article] [PubMed]
    [Google Scholar]
  6. Enjalbert B, Smith DA, Cornell MJ, Alam I, Nicholls S et al. Role of the Hog1 stress-activated protein kinase in the global transcriptional response to stress in the fungal pathogen Candida albicans. Mol Biol Cell 2006; 17:1018–1032 [View Article] [PubMed]
    [Google Scholar]
  7. Román E, Correia I, Prieto D, Alonso R, Pla J et al. The HOG MAPK pathway in Candida albicans: more than an osmosensing pathway. Int Microbiol 2020; 23:23–29 [View Article] [PubMed]
    [Google Scholar]
  8. Correia I, Alonso-Monge R, Pla J. The Hog1 MAP kinase promotes the recovery from cell cycle arrest induced by hydrogen peroxide in Candida albicans. Front Microbiol 2016; 7:2133 [View Article] [PubMed]
    [Google Scholar]
  9. Lee YM, Kim E, An J, Lee Y, Choi E et al. Dissection of the HOG pathway activated by hydrogen peroxide in Saccharomyces cerevisiae. Environ Microbiol 2017; 19:584–597 [View Article] [PubMed]
    [Google Scholar]
  10. Su C, Lu Y, Liu H. Reduced TOR signaling sustains hyphal development in Candida albicans by lowering Hog1 basal activity. Mol Biol Cell 2013; 24:385–397 [View Article] [PubMed]
    [Google Scholar]
  11. Alonso-Monge R, Carvaihlo S, Nombela C, Rial E, Pla J et al. The Hog1 MAP kinase controls respiratory metabolism in the fungal pathogen Candida albicans. Microbiology (Reading) 2009; 155:413–423 [View Article] [PubMed]
    [Google Scholar]
  12. Morales-Menchén A, Navarro-García F, Guirao-Abad JP, Román E, Prieto D et al. Non-canonical activities of Hog1 control sensitivity of Candida albicans to killer toxins from Debaryomyces hansenii. Front Cell Infect Microbiol 2018; 8:135 [View Article] [PubMed]
    [Google Scholar]
  13. He J-M, Sun S-C, Sun Z-L, Chen J-T, Mu Q et al. Isovalerylshikonin, a new resistance-modifying agent from Arnebia euchroma, supresses antimicrobial resistance of drug-resistant Staphylococcus aureus. Int J Antimicrob Agents 2019; 53:70–73 [View Article] [PubMed]
    [Google Scholar]
  14. Yang K, Zhang Y. Reversal of heavy metal-induced antibiotic resistance by dandelion root extracts and taraxasterol. J Med Microbiol 2020; 69:1049–1061 [View Article] [PubMed]
    [Google Scholar]
  15. Warowicka A, Nawrot R, Goździcka-Józefiak A. Antiviral activity of berberine. Arch Virol 2020; 165:1935–1945 [View Article] [PubMed]
    [Google Scholar]
  16. Hou Q, He W-J, Wu Y-S, Hao H-J, Xie X-Y et al. Berberine: a traditional natural product with novel biological activities. Altern Ther Health Med 2020; 26:20–27 [PubMed]
    [Google Scholar]
  17. Chu M, Zhang M-B, Liu Y-C, Kang J-R, Chu Z-Y et al. Role of berberine in the treatment of methicillin-resistant Staphylococcus aureus infections. Sci Rep 2016; 6:24748 [View Article] [PubMed]
    [Google Scholar]
  18. Chen L, Bu Q, Xu H, Liu Y, She P et al. The effect of berberine hydrochloride on Enterococcus faecalis biofilm formation and dispersion in vitro. Microbiol Res 2016; 186–187:44–51 [View Article] [PubMed]
    [Google Scholar]
  19. Cernáková M, Kostálová D. Antimicrobial activity of berberine--a constituent of Mahonia aquifolium. Folia Microbiol (Praha) 2002; 47:375–378 [View Article] [PubMed]
    [Google Scholar]
  20. Poopedi E, Marimani M, AlOmar SY, Aldahmash B, Ahmad A. Modulation of antioxidant defence system in response to berberine in Candida albicans. Yeast 2021; 38:157–169 [View Article] [PubMed]
    [Google Scholar]
  21. Yong J, Zu R, Huang X, Ge Y, Li Y et al. Synergistic effect of berberine hydrochloride and fluconazole against Candida albicans resistant isolates. Front Microbiol 2020; 11:1498 [View Article] [PubMed]
    [Google Scholar]
  22. CLSI Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. 4th ed. CLSI standard M27 Wayne, PA: Clinical and Laboratory Standards Institute; 2017
    [Google Scholar]
  23. Hu T-L, Yun Y, Xu Z-Q, Duan Q-J, Shao J et al. Butyl alcohol extract of Baitouweng decoction inhibits Candida albicans cell membrane. Zhongguo Zhong Yao Za Zhi 2017; 42:3182–3190 [View Article] [PubMed]
    [Google Scholar]
  24. Zorić N, Kosalec I, Tomić S, Bobnjarić I, Jug M et al. Membrane of Candida albicans as a target of berberine. BMC Complement Altern Med 2017; 17:268 [View Article] [PubMed]
    [Google Scholar]
  25. Özdemir A, Altıntop MD, Sever B, Gençer HK, Kapkaç HA et al. A new series of pyrrole-based chalcones: synthesis and evaluation of antimicrobial activity, cytotoxicity, and genotoxicity. Molecules 2017; 22:E2112 [View Article] [PubMed]
    [Google Scholar]
  26. Nakamura A, Takigawa K, Kurishita Y, Kuwata K, Ishida M et al. Hoechst tagging: a modular strategy to design synthetic fluorescent probes for live-cell nucleus imaging. Chem Commun (Camb) 2014; 50:6149–6152 [View Article] [PubMed]
    [Google Scholar]
  27. Zhao XY, Guo G, Su PP et al. Inhibitory effect of housefly antimicrobial peptide AMP-17 on hyphae of Candida albicans. Microbiology China 2019; 12:1–15 [View Article]
    [Google Scholar]
  28. Li Y, Sun H, Zhu X, Bian C, Wang Y et al. Identification of new antifungal agents targeting chitin synthesis by a chemical-genetic method. Molecules 2019; 24:E3155 [View Article] [PubMed]
    [Google Scholar]
  29. Liu YF, Tang QJ, Zhang JS et al. Determination of β-(1,3) glucan content and analysis of polysaccharide composition from ganoderma lingzhi extract. Mycosystema 2018; 37:1525–1531
    [Google Scholar]
  30. Haque F, Alfatah M, Ganesan K, Bhattacharyya MS et al. Inhibitory effect of sophorolipid on Candida albicans biofilm formation and hyphal growth. Sci Rep 2016; 6:23575 [View Article] [PubMed]
    [Google Scholar]
  31. Mancuso R, Chinnici J, Tsou C et al. Functions of Candida albicans cell wall glycosidases dfg5p and dcw1p in biofilm formation and HOG MAPK pathway. PeerJ 2018; 6:e5685 [View Article]
    [Google Scholar]
  32. Guerra-Moreno A, Ang J, Welsch H, Jochem M, Hanna J et al. Regulation of the unfolded protein response in yeast by oxidative stress. FEBS Lett 2019; 593:1080–1088 [View Article] [PubMed]
    [Google Scholar]
  33. Liu N-N, Uppuluri P, Broggi A, Besold A, Ryman K et al. Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence. PLoS Pathog 2018; 14:e1007076 [View Article] [PubMed]
    [Google Scholar]
  34. Alam Shibly SU, Ghatak C, Sayem Karal MA, Moniruzzaman M, Yamazaki M et al. Experimental estimation of membrane tension induced by osmotic pressure. Biophys J 2016; 111:2190–2201 [View Article] [PubMed]
    [Google Scholar]
  35. Gregori C, Schüller C, Roetzer A, Schwarzmüller T, Ammerer G et al. The high-osmolarity glycerol response pathway in the human fungal pathogen Candida glabrata strain ATCC 2001 lacks a signaling branch that operates in baker’s yeast. Eukaryot Cell 2007; 6:1635–1645 [View Article] [PubMed]
    [Google Scholar]
  36. Hohmann S. An integrated view on a eukaryotic osmoregulation system. Curr Genet 2015; 61:373–382 [View Article] [PubMed]
    [Google Scholar]
  37. Hwang B, Hwang J-S, Lee J, Kim J-K, Kim SR et al. Induction of yeast apoptosis by an antimicrobial peptide, Papiliocin. Biochem Biophys Res Commun 2011; 408:89–93 [View Article] [PubMed]
    [Google Scholar]
  38. Seyedjavadi SS, Khani S, Eslamifar A, Ajdary S, Goudarzi M et al. The antifungal peptide MCh-AMP1 derived from Matricaria chamomilla inhibits Candida albicans growth via inducing ROS generation and altering fungal cell membrane permeability. Front Microbiol 2019; 10:3150 [View Article] [PubMed]
    [Google Scholar]
  39. Vogt S, Rhiel A, Weber P, Ramzan R et al. Revisiting Kadenbach: Electron flux rate through cytochrome c-oxidase determines the ATP-inhibitory effect and subsequent production of ROS. Bioessays 2016; 38:556–567 [View Article] [PubMed]
    [Google Scholar]
  40. Wang ZG, Ackerman SH. Identification of functional domains in Atp11p. Protein required for assembly of the mitochondrial F1-ATPase in yeast. J Biol Chem 1996; 271:4887–4894 [View Article] [PubMed]
    [Google Scholar]
  41. Lefebvre-Legendre L, Salin B, Schaëffer J, Brèthes D, Dautant A et al. Failure to assemble the alpha 3 beta 3 subcomplex of the ATP synthase leads to accumulation of the alpha and beta subunits within inclusion bodies and the loss of mitochondrial cristae in Saccharomyces cerevisiae. J Biol Chem 2005; 280:18386–18392 [View Article] [PubMed]
    [Google Scholar]
  42. Netto LES, Antunes F. The roles of peroxiredoxin and thioredoxin in hydrogen peroxide sensing and in signal transduction. Mol Cells 2016; 39:65–71 [View Article] [PubMed]
    [Google Scholar]
  43. Silva S, Rodrigues CF, Araújo D, Rodrigues ME, Henriques M et al. Candida species biofilms’ antifungal resistance. J Fungi (Basel) 2017; 3:E8 [View Article] [PubMed]
    [Google Scholar]
  44. Nailis H, Vandenbosch D, Deforce D, Nelis HJ, Coenye T et al. Transcriptional response to fluconazole and amphotericin B in Candida albicans biofilms. Res Microbiol 2010; 161:284–292 [View Article] [PubMed]
    [Google Scholar]
  45. Sharma J, Rosiana S, Razzaq I, Shapiro RS et al. Linking cellular morphogenesis with antifungal treatment and susceptibility in Candida pathogens. J Fungi (Basel) 2019; 5:E17 [View Article] [PubMed]
    [Google Scholar]
  46. Wu J, Wu D, Zhao Y, Si Y, Mei L et al. Sodium new houttuyfonate inhibits Candida albicans biofilm formation by inhibiting the Ras1-cAMP-Efg1 pathway revealed by RNA-seq. Front Microbiol 2020; 11:2075 [View Article] [PubMed]
    [Google Scholar]
  47. Shin DS, Eom YB. Zerumbone inhibits Candida albicans biofilm formation and hyphal growth. Can J Microbiol 2019; 65:713–721 [View Article] [PubMed]
    [Google Scholar]
  48. Childers DS, Avelar GM, Bain JM, Larcombe DE, Pradhan A et al. Impact of the Environment upon the Candida albicans cell wall and resultant effects upon immune surveillance. Curr Top Microbiol Immunol 2020; 425:297–330 [View Article] [PubMed]
    [Google Scholar]
  49. Ene IV, Walker LA, Schiavone M, Lee KK, Martin-Yken H et al. Cell wall remodeling enzymes modulate fungal cell wall elasticity and osmotic stress resistance. mBio 2015; 6:e00986 [View Article] [PubMed]
    [Google Scholar]
  50. Lee HS, Kim Y. Aucklandia lappa causes cell wall damage in candida albicans by reducing chitin and (1,3)-β-D-glucan. J Microbiol Biotechnol 2020; 30:967–973 [View Article] [PubMed]
    [Google Scholar]
  51. Knafler HC, Smaczynska-de Rooij II, Walker LA, Lee KK, Gow NAR et al. AP-2-dependent endocytic recycling of the chitin synthase Chs3 regulates polarized growth in Candida albicans. mBio 2019; 10:e02421-18 [View Article] [PubMed]
    [Google Scholar]
  52. Orlean P. Architecture and biosynthesis of the Saccharomyces cerevisiae cell wall. Genetics 2012; 192:775–818 [View Article] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.001542
Loading
/content/journal/jmm/10.1099/jmm.0.001542
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error