Active Cu(II), Mn(II) and Ag(I) 1,10-phenanthroline/1,10-phenanthroline-5,6-dione/dicarboxylate chelates: effects on Scedosporium
Abstract
Background:Scedosporium/Lomentospora species are human pathogens that are resistant to almost all antifungals currently available in clinical practice. Methods: The effects of 16 1,10-phenanthroline (phen)/1,10-phenanthroline-5,6-dione/dicarboxylate chelates containing Cu(II), Mn(II) and Ag(I) against Scedosporium apiospermum, Scedosporium minutisporum, Scedosporium aurantiacum and Lomentospora prolificans were evaluated. Results: To different degrees, all of the test chelates inhibited the viability of planktonic conidial cells, displaying MICs ranging from 0.029 to 72.08 μM. Generally, Mn(II)-containing chelates were the least toxic to lung epithelial cells, particularly [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2].4H2O (MICs: 1.62–3.25 μM: selectivity indexes >64). Moreover, this manganese-based chelate reduced the biofilm biomass formation and diminished the mature biofilm viability. Conclusion: [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2].4H2O opens a new chemotherapeutic avenue for the deactivation of these emergent, multidrug-resistant filamentous fungi.
Plain language summary
Metals have been used to treat microbial infections for centuries. In this context, the effects of 16 metal-based compounds against the human pathogens Scedosporium apiospermum, Scedosporium minutisporum, Scedosporium aurantiacum and Lomentospora prolificans were tested. All the 16 metal-based compounds were able to interfere with the viability of these fungal pathogens to different degrees. Among the 16 compounds, a manganese-containing compound presented the best activity against the fungal species and it presented the least toxicity to a human lung cell line. In addition, this manganese-containing compound reduced the ability of fungal cells to come together and form a type of community called biofilm. In conclusion, the manganese-containing compound presents a promising option against the multidrug-resistant filamentous fungi species belonging to the Scedosporium/Lomentospora genera.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Emerging fungal infections: new patients, new patterns, and new pathogens. J. Fungi (Basel) 5(3), 67 (2019).
- 2. Infections caused by Scedosporium spp. Clin. Microbiol. Rev. 21(1), 157–197 (2008).
- 3. . Ecology of Pseudallescheria and Scedosporium species in human-dominated and natural environments and their distribution in clinical samples. Med. Mycol. 47(4), 398–405 (2009).
- 4. . Distribution of Scedosporium species in soil from areas with high human population density and tourist popularity in six geographic regions in Thailand. PLOS ONE 14(1), e0210942 (2019).
- 5. Scedosporium and Lomentospora: an updated overview of underrated opportunists. Med. Mycol. 56(Suppl. 1), 102–125 (2018). •• An excellent overview about Scedosporium species.
- 6. Advances in understanding and managing Scedosporium respiratory infections in patients with cystic fibrosis. Expert Rev. Respir. Med. 14(3), 259–273 (2019).
- 7. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: Fusarium spp., Scedosporium spp. and others. Clin. Microbiol. Infect. 20(Suppl. 3), 27–46 (2014).
- 8. Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008–2019. Clin. Microbiol. Infect. 26(6), 784.e1–784.e5 (2020).
- 9. The characteristics of Aspergillus fumigatus mycetoma development: is this a biofilm? Med. Mycol. 47(Suppl. 1), S120–S126 (2009).
- 10. Assessment of biofilm formation by Scedosporium apiospermum, S. aurantiacum, S. minutisporum and Lomentospora prolificans. Biofouling 32, 737–749 (2016).
- 11. Impact of biofilm formation and azoles' susceptibility in Scedosporium/Lomentospora species using an in vitro model that mimics the cystic fibrosis patients’ airway environment. J. Cyst. Fibros. 20, 303–309 (2021).
- 12. Biofilm formation by Pseudallescheria/Scedosporium species: a comparative study. Front. Microbiol. 8, 1568 (2017).
- 13. Antimicrobial action of chelating agents: repercussions on the microorganism development, virulence and pathogenesis. Curr. Med. Chem. 19, 2715–2737 (2012).
- 14. The antibacterial activity of metal complexes containing 1,10-phenanthroline: potential as alternative therapeutics in the era of antibiotic resistance. Curr. Top. Med. Chem. 17(11), 1280–1302 (2017). •• An excellent overview about antimicrobial properties of phenanthroline chelators.
- 15. Deciphering the antimicrobial activity of phenanthroline chelators. Curr. Med. Chem. 19(17), 2703–2714 (2012).
- 16. In vivo activity of copper(II), manganese(II), and silver(I) 1,10-phenanthroline chelates against Candida haemulonii using the Galleria mellonella model. Front. Microbiol. 11, 470 (2020).
- 17. Silver(I) and copper(II) complexes of 1,10-phenanthroline-5,6-dione against Phialophora verrucosa: a focus on the interaction with human macrophages and Galleria mellonella larvae. Front. Microbiol. 12, 641258 (2021).
- 18. Synthesis and antimicrobial activity of copper(II) and manganese(II) α,ω-dicarboxylate complexes. Biometals 13, 1–8 (2000).
- 19. Insights into the mode of action of the anti-Candida activity of 1,10-phenanthroline and its metal chelates. Met. Based Drugs 7, 185–193 (2000).
- 20. Mode of anti-fungal activity of 1,10-phenanthroline and its Cu(II), Mn(II) and Ag(I) complexes. Biometals 16, 321–329 (2003).
- 21. Clinical isolates of Candida albicans, Candida tropicalis, and Candida krusei have different susceptibilities to Co(II) and Cu(II) complexes of 1,10-phenanthroline. Biometals 28, 415–423 (2015).
- 22. Anti-Pseudomonas aeruginosa activity of 1,10-phenanthroline-based drugs against both planktonic- and biofilm-growing cells. J. Antimicrob. Chemother. 71, 128–134 (2016).
- 23. Disarming Pseudomonas aeruginosa virulence by the inhibitory action of 1,10-phenanthroline-5,6-dione-based compounds: elastase B (LasB) as a chemotherapeutic target. Front. Microbiol. 10, 1701 (2019).
- 24. Antifungal potential of copper(II), manganese(II) and silver(I) 1,10-phenanthroline chelates against multidrug-resistant fungal species forming the Candida haemulonii complex: impact on the planktonic and biofilm lifestyles. Front. Microbiol. 8, 1257 (2017).
- 25. 1,10-Phenanthroline-5,6-dione-based compounds are effective in disturbing crucial physiological events of Phialophora verrucosa. Front. Microbiol. 8, 76 (2017).
- 26. Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs. Front. Microbiol. 9, 1432 (2018).
- 27. Synthesis and X-ray crystal structure of [Ag(phendio)2]ClO4 (phendio = 1,10-phenanthroline-5,6-dione) and its effects on fungal and mammalian cells. Biometals 17, 635–645 (2004).
- 28. Synthesis, characterisation and antimicrobial activity of copper(II) and manganese(II) complexes of coumarin-6,7-dioxyacetic acid (cdoaH2) and 4-methylcoumarin-6,7-dioxyacetic acid (4-MecdoaH2): x-ray crystal structures of [Cu(cdoa)(phen)2].8.8H2O and [Cu(4-Mecdoa)(phen)2].13H2O (phen = 1,10-phenanthroline). J. Inorg. Biochem. 101, 1108–1119 (2007).
- 29. Conidial germination in Scedosporium apiospermum, S. aurantiacum, S. minutisporum and L. prolificans: influence of growth conditions and antifungal susceptibility profiles. Mem. Inst. Oswaldo Cruz 111(7), 484–494 (2016).
- 30. Synthesis and structure of the Mn2 (II,II) complex salt [Mn2(oda)(phen)4(H2O)2] [Mn2(oda)2(phen)4] (odaH2 = octanedioic acid): a catalyst for H2O2 disproportionation. J. Chem. Soc. Chem. Commun. 22, 2643–2645 (1994).
- 31. Binuclear and polymeric copper(II) dicarboxylate complexes: synthesis and crystal structures of [Cu2(pda)(phen)4](ClO4)2.5H2O.EtOH, [Cu2(oda)(phen)4](ClO4)2.2.67H2O.EtOH and {Cu2(pda)2(NH3)4(H2O)2.4H2O}n (odaH2 = octanedioic acid; pdaH2 = pentanedioic acid; phen = 1,10-phenanthroline). Polyhedron 18, 2141–2148 (1999).
- 32. Synthesis and biological activity of manganese(II) complexes of phthalic and isophthalic acid: x-ray crystal structures of [Mn(ph)(Phen)2(H2O)].4H2O, [Mn(Phen)2(H2O)2]2 (Isoph)2(Phen)·14H2O and {[Mn(Isoph)(bipy)2]4.2.75bipy}n (phH2 = phthalic acid; Isoph = isophthalic acid; Phen = 1,10-phenanthroline; bipy = 2,2-bipyridine). Met. Based Drugs 7, 275–288 (2000).
- 33. . Synthesis, characterization and catalytic and biological activity of new manganese(II) carboxylate complexes [dissertation]. Dublin Institute of Technology, Dublin, D, Ireland (2000).
- 34. Manganese(II) complexes of 3,6,9-trioxaundecanedioic acid (3,6,9-tddaH2): x-ray crystal structures of [Mn(3,6,9-tdda)(H2O)2].2H2O and {[Mn(3,6,9-tdda)(phen)2].3H2O.EtOH}n. Polyhedron 16, 4247–4252 (1997).
- 35. Bis-phenanthroline copper(II) phthalate complexes are potent in vitro antitumour agents with ‘self-activating’ metallo-nuclease and DNA binding properties. Dalton Trans. 40, 1024–1027 (2011).
- 36. Radical induced DNA damage by cytotoxic square-planar copper(II) complexes incorporating o-phthalate and 1,10-phenanthroline or 2,2′-dipyridyl. Free Radic. Biol. Med. 53, 564–576 (2012).
- 37. Water-soluble and photo-stable silver(I) dicarboxylate complexes containing 1,10-phenanthroline ligands: antimicrobial and anticancer chemotherapeutic potential, DNA interactions and antioxidant activity. J. Inorg. Biochem. 159, 120–132 (2016).
- 38. Clinical Laboratory Standards Institute. CLSI Document M38-A2. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standard (2nd Edition). PA, USA, 52 (2008).
- 39. . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 65, 55–63 (1983).
- 40. Aspergillus biofilms: clinical and industrial significance. FEMS Microbiol. Lett. 324, 89–97 (2011).
- 41. Insights into the social life and obscure side of Scedosporium/Lomentospora species: ubiquitous, emerging and multidrug-resistant opportunistic pathogens. Fungal Biol. Rev. 33(1), 16–46 (2018).
- 42. . Kinetically inert transition metal complexes that reversibly bind to DNA. Chem. Soc. Rev. 32, 215–224 (2003).
- 43. In vitro and in vivo studies into the biological activities of 1,10-phenanthroline, 1,10-phenanthroline-5,6-dione and its copper(II) and silver(I) complexes. Toxicol. Res. 1, 47–54 (2012).
- 44. Metal complexes containing natural and artificial radioactive elements and their applications. Molecules 19, 10755–10802 (2019).
- 45. In vitro anti-tumour effect of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2.4H2O and [Ag(phendione)2]ClO4 using human epithelial cell lines. Chem. Biol. Interact. 164, 115–125 (2006).
- 46. Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa. J. Biol. Inorg. Chem. 27(1), 201–213 (2022).
- 47. Metallopeptidase inhibitors arrest vital biological processes in the fungal pathogen Scedosporium apiospermum. Mycoses 54, 105–112 (2011).
- 48. . Antimicrobial activity of metals: mechanisms, molecular targets and applications. Nat. Rev. Microbiol. 11(6), 371–384 (2013).
- 49. . Biofilms formed by Scedosporium and Lomentospora species: focus on the extracellular matrix. Biofouling 36, 308–318 (2020).
- 50. Decoding the antifungal resistance mechanisms in biofilms of emerging, ubiquitous and multidrug-resistant species belonging to the Scedosporium/Lomentospora genera. Med. Mycol. 60(6), myac036 (2022).
- 51. Fungal biofilm resistance. Int. J. Microbiol. 2012, 528521 (2012). •Overview of mechanisms of resistance found in fungal biofilms.
- 52. Antibiofilm activity of antifungal drugs, including the novel drug olorofim, against Lomentospora prolificans. J. Antimicrob. Chemother. 75(8), 2133–2140 (2020). • Describes the effect of the notable compound olorofim against the multidrug-resistant Lomentospora prolificans.
- 53. Determination and prediction of permeability across intestinal epithelial cell monolayer of a diverse range of industrial chemicals/drugs for estimation of oral absorption as a putative marker of hepatotoxicity. Toxicol. Rep. 7, 149–154 (2020).
- 54. . The importance of plasma protein binding in drug discovery. Expert Opin. Drug Discov. 2(1), 51–64 (2007).
- 55. . Design, synthesis, stereochemical determination, molecular docking study, in silico pre-ADMET prediction and anti-proliferative activities of indole-pyrimidine derivatives as Mcl-1 inhibitors. Bioorg. Chem. 116, 105335 (2021).