The current global scenario presents us with a growing increase in infections caused by fungi, referred to by specialists in the field as a "silent epidemic", aggravated by the limited pharmacological arsenal and increasing resistance to this therapy. For this reason, drug repositioning and therapeutic compound combinations are promising strategies to mitigate this serious problem. In this context, this study investigates the antifungal activity of the non-toxic, low-cost and widely available cationic polyelectrolyte Poly(diallyldimethylammonium chloride) (PDDA), in combination with different antifungal drugs: systemic (amphotericin B, AMB), topical (clioquinol, CLIO) and oral (nitroxoline, NTX). For each combination, different drug:PDDA ratios were tested and, through the broth microdilution technique, the minimum inhibitory concentration (MIC) of these drugs in the different ratios against clinically important Candida species strains was determined. Overall, PDDA combinations with the studied drugs demonstrated a significant increase in drug activity against most strains, reaching MIC reductions of up to 512 fold for the fluconazole resistant Candida krusei (Pichia kudriavzevii). In particular, the AMB-PDDA combination 1:99 was highly effective against AMB-resistant strains, demonstrating the excellent profile of PDDA as an adjuvant/association in novel antifungal formulations with outdated conventional drugs.

Department of Inorganic Chemistry Faculty of Science Charles University Hlavova 2030 8 Prague 128 00 Czech Republic

Institute of Inorganic Chemistry of the Czech Academy of Sciences Husinec Řež 1001 250 68 Řež Czech Republic

Laboratório de Pesquisa Em Micologia Aplicada Universidade Federal Do Rio Grande Do Sul Rua São Luís 152 Porto Alegre 90470 440 Brazil

Programa de Pós Graduação Em Ciências Farmacêuticas Universidade Federal Do Rio Grande Do Sul Av Ipiranga 2752 Porto Alegre 90610 000 Brazil

Zobrazit více v PubMed

World Health Organization (2022) Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report 2022

Zhu P, Li Y, Guo T, et al (2023) New antifungal strategies: Drug combination and co-delivery. Adv Drug Deliv Rev 198

Hsu AY, Lin C-J (2024) The Taiwan health-care system: approaching a crisis point? Lancet 404:745–746 PubMed DOI

World Health Organization. (2023) Antimicrobial resistance

Heard SC, Wu G, Winter JM (2021) Antifungal natural products. Curr Opin Biotechnol 69:232–241 PubMed DOI

Fisher MC, Alastruey-Izquierdo A, Berman J et al (2022) Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol 20:557–571 PubMed DOI PMC

Lionakis MS, Drummond RA, Hohl TM (2023) Immune responses to human fungal pathogens and therapeutic prospects. Nat Rev Immunol 23:433–452 PubMed DOI

World Health Organization (2022) WHO fungal priority pathogens list to guide research, development and public health action

Hoenigl M, Sprute R, Egger M et al (2021) The antifungal pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin. Drugs 81:1703–1729. https://doi.org/10.1007/s40265-021-01611-0 PubMed DOI PMC

Zhang Z, Bills GF, An Z (2023) Advances in the treatment of invasive fungal disease. PLoS Pathog. https://doi.org/10.1371/journal.ppat.1011322 PubMed DOI PMC

The Lancet Infectious Diseases (2023) An exciting time for antifungal therapy. The Lancet

Fuentefria AM, Pippi B, Dalla Lana DF et al (2018) Antifungals discovery: an insight into new strategies to combat antifungal resistance. Lett Appl Microbiol 66:2–13 PubMed DOI

Du W, Gao Y, Liu L et al (2021) Striking back against fungal infections: The utilization of nanosystems for antifungal strategies. Int J Mol Sci. https://doi.org/10.3390/ijms221810104 PubMed DOI PMC

Wu S, Guo W, Li B et al (2023) Progress of polymer-based strategies in fungal disease management: designed for different roles. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2023.1142029 PubMed DOI PMC

Bayliss N, Schmidt BVKJ (2023) Hydrophilic polymers: Current trends and visions for the future. Prog Polym Sci. https://doi.org/10.1016/j.progpolymsci.2023.101753 DOI

dos Santos R, Sarra G, Lincopan N et al (2021) Preparation, antimicrobial properties, and cytotoxicity of Acrylic Resins containing Poly(diallyldimethylammonium chloride). Int J Prosthodont 34:635–641. https://doi.org/10.11607/ijp.6506 PubMed DOI

Biery AR, Knauss DM (2022) Recent advances in the synthesis of diallylammonium polymers. Mater Today Chem 26

Kamiński K, Hąc-Wydro K, Skóra M et al (2022) Preliminary studies on the mechanism of antifungal activity of new cationic β-Glucan derivatives obtained from Oats and Barley. ACS Omega 7:40333–40343. https://doi.org/10.1021/acsomega.2c05311 PubMed DOI PMC

Timofeeva LM, Kleshcheva NA, Moroz AF, Didenko LV (2009) Secondary and tertiary polydiallylammonium salts: novel polymers with high antimicrobial activity. Biomacromol 10:2976–2986. https://doi.org/10.1021/bm900435v DOI

de Carvalho GR, Delarmelina C, Duarte MCT et al (2024) Novel composite film based on cassava starch and poly (diallyldimethylammonium chloride) reinforced with nanocrystalline cellulose for bacteria and coronavirus inactivation. Polym Bull 81:14049–14066 DOI

Panáček A, Balzerová A, Prucek R et al (2013) Preparation, characterization and antimicrobial efficiency of Ag/PDDA-diatomite nanocomposite. Coll Surf B Biointerf 110:191–198. https://doi.org/10.1016/j.colsurfb.2013.04.031 DOI

Clinical and Laboratory Standards Institute. (2008) Reference method for broth dilution antifungal susceptibility testing of yeasts. Clinical and Laboratory Standards Institute

Clinical and Laboratory Standards Institute. (2012) Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts

Pfaller MA, Espinel-Ingroff A, Canton E et al (2012) Wild-type MIC distributions and epidemiological cutoff values for amphotericin B, flucytosine, and itraconazole and Candida spp. as determined by CLSI broth microdilution. J Clin Microbiol 50:2040–2046. https://doi.org/10.1128/JCM.00248-12 PubMed DOI PMC

Kranz J, Helbig S, Mandraka F et al (2017) The revival of old antibiotics for treatment of uncomplicated urinary tract infections in the era of antibiotic stewardship. Curr Opin Urol 27:127–132 PubMed DOI

Pippi B, Reginatto P, MacHado DRM, G, et al (2017) Evaluation of 8-Hydroxyquinoline derivatives as hits for antifungal drug design. Med Mycol 55:763–773. https://doi.org/10.1093/mmy/myx003 PubMed DOI

R Core Team (2018) R: A language and environment for statistical computing. In: R Foundation for Statistical Computing

Pérez-Betancourt Y, Zaia R, Evangelista MF et al (2022) Characterization and differential cytotoxicity of gramicidin nanoparticles combined with cationic polymer or lipid bilayer. Pharmaceutics. https://doi.org/10.3390/pharmaceutics14102053 PubMed DOI PMC

de Carvalho GR, Kudaka AM, Netto RA et al (2023) Antiviral and antibacterial activity of sodium alginate/poly(diallyldimethylammonium chloride) polyelectrolyte film for packaging applications. Int J Biol Macromol. https://doi.org/10.1016/j.ijbiomac.2023.125388 PubMed DOI PMC

Sanches LM, Petri DFS, Melo Carrasco LD, Carmona-Ribeiro AM (2015) The antimicrobial activity of free and immobilized poly (diallyldimethylammonium) chloride in nanoparticles of poly (methylmethacrylate). J Nanobiotechnology. https://doi.org/10.1186/s12951-015-0123-3 PubMed DOI PMC

Melo LD, Carmona-Ribeiro AM (2012) Fungicidal nanoparticles of low toxicity from cationic lipid and polyelectrolytes. NSTI-Nanotech

Cavassin FB, Baú-Carneiro JL, Vilas-Boas RR, Queiroz-Telles F (2021) Sixty years of Amphotericin B: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections. Infect Dis Ther 10:115–147 PubMed DOI PMC

Pippi B, Merkel S, Staudt KJ et al (2019) Oral clioquinol is effective in the treatment of a fly model of Candida systemic infection. Mycoses 62:475–481. https://doi.org/10.1111/myc.12888 PubMed DOI

Fuchs F, Aldejohann AM, Hoffmann AM et al (2022) In Vitro Activity of Nitroxoline in Antifungal-Resistant Candida Species Isolated from the Urinary Tract. Antimicrob Agents Chemother. https://doi.org/10.1128/aac.02265-21 PubMed DOI PMC

Musiol R, Serda M, Hensel-Bielowka S, Polanski J (2010) Quinoline-Based Antifungals

You Z, Zhang C, Ran Y (2020) The effects of clioquinol in morphogenesis, cell membrane and ion homeostasis in Candida albicans. BMC Microbiol. https://doi.org/10.1186/s12866-020-01850-3 PubMed DOI PMC

Padilla-Garfias F, Ríos-Cifuentes L, Sánchez NS et al (2022) Study of the mechanism of ε-poly-L-lysine as an antifungal on Candida albicans and Saccharomyces cerevisiae. Biochim Biophys Acta Gen Subj. https://doi.org/10.1016/j.bbagen.2022.130197 PubMed DOI