Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole

Abstract

In this study, we found that ambroxol hydrochloride (128 μg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 μg/mL) against resistant planktonic Candida albicans (C. albicans) cells. This combination also exhibited synergistic effects against resistant C. albicans biofilms in different stages (4, 8, and 12 h) according to the microdilution method. In vitro data were further confirmed by the success of this combination in treating Galleria mellonella infected by resistant C. albicans. With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant C. albicans, increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the in vitro and in vivo antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant C. albicans. The results show the potential role for this drug combination as a therapeutic alternative to treat resistant C. albicans and provide insights into the development of antifungal targets and new antifungal agents.

Pathogenesis and Clinical Relevance of Candida Biofilms in Vulvovaginal Candidiasis

“…cells It is able to prevent biofilm formation by C. albicans and C. parapsilosis both in vitro and in vivo Application in medical devices Silva-Dias et al, 2015 Fluconazole analogs with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents These compounds are active against some of the C. albicans and non-albicans Candida strains and are highly effective against clinical strains of C. glabrata and C. parapsilosis Micafungin + ethanol Capsofungin/posaconazole, or amphotericin B, or anidulafungin, or Caspofungin/micafungin in combination with nikkomycin Z Antifungal lock therapy is used to inhibit the formation of the biofilm Walraven and Lee, 2013Basas et al, 2019Kovács et al, 2019 27 new FLC derivatives Broad-spectrum antifungal activity. All compounds inhibit the sterol 14α-demethylase enzyme involved in ergosterol biosynthesis Shrestha et al, 2017 Fluoroquinolones and antifungal agents (from amphotericin B or caspofungin) or rifampicin Chloramphenicol Very useful in immunosuppressed patients Stergiopoulou et al, 2009Vogel et al, 2008 Not valid for use against C. albicans or C. glabrata Antifungal activity comparable to caspofungin and ketoconazole Joseph et al, 2015 Tyrosol and farnesol Strong biofilm inhibition Inhibit the formation of hyphae Monteiro et al, 2017Mehmood et al, 2019 Amphotericin B plus silver hybrid nanoparticles Powerful antifungal activity although the toxicity of the nanoparticles depends on the size, concentration, and pH of the medium and the exposure time to pathogens Leonhard et al, 2018 Amphotericin B plus acetylsalicylic/ibuprofen/ambroxol They are inexpensive, but they increase the risk of bleeding and hyperkalaemia Zhou et al, 2012Sharma et al, 2015Li et al, 2017 KSL-W and SM21 peptides Inhibit biofilm formation by Candida spp. Theberge et al, 2013 Cavalheiro andTeixeira, 2018 is also no consensus on which specific strains of Lactobacillus may be most beneficial for dysbiosis.…”

Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

“…Antifungal combinations against Candida spp. have also been explored in the G. mellonella model [18,[35][36][37][38][39][40][41][42][43][44]73].…”

“…Several other studies (Table 2) used G. mellonella to demonstrate synergistic interactions between antifungals (mainly fluconazole) and other drugs against C. albicans [35,[37][38][39][40]43,44,73]. The partner drugs were anti-inflammatory compounds such as dexamethasone [43] and licofelone [40], Dpenicillamine, a heavy metal chelator [39], harmine, an alkaloid with multiple pharmacological properties [37], ambroxol, a mucolytic drug [38], antivirals such as ribavirin [44], proton-pump inhibitors [73], or Hsp-90 (a molecular chaperone implicated in cellular response to stress) inhibitors [35].…”

Antifungal Activity and Potential Mechanism of Panobinostat in Combination With Fluconazole Against Candida albicans

“…Combination drug therapy is a promising strategy to increase effectiveness of antifungals and alleviate the emergence of drug resistance ( Spitzer et al, 2017 ; Arita et al, 2019 ). Over the past few years, many efforts have been made to prove that drug combination is an optional approach for overcoming drug resistance and treatment of invasive fungal infections, and the results indicate that non-antifungal drugs can significantly increase the sensitivity of azoles regardless of whether they have antifungal effects or not by themselves ( Li et al, 2017 ; Li Y. et al, 2019 ; Gong et al, 2019b ).…”