An upfront strategy to potentiate the biological activity of antifungal drugs

Funding Information: This work was nancially supported by Fundação para a Ciência e a Tecnologia (FCT) by Project MOSTMICRO ITQB with refs UIDB/04612/2020 and UIDP/04612/2020, and by the European Research Council through grant ERC 2014-CoG-647928. The authors thank FCT for funding the Research Unit Centro de Qúımica Estrutural (UIDB/00100/2020 and UIDP/00100/2020) and project PTDC/QUI-QFI/29527/2017, and PT2020 Partnership Agreement for project Lisboa/01/0145/FEDER/028367. The authors thank Associate Laboratory for Green Chemistry-LAQV which is nanced by national funds from FCT/MCTES (UIDB/ 50006/2020) and co-nanced by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER – 007265), to FCT (PTDC/QUI-QOR/32406/2017) and MAR2020 (MAR-02.01.01-FEAMP-0042 – INOVA4AQUA). DOH, MR and MP are grateful for the fellowships SFRH/BPD/121354/2016, SFRH/BD/113989/ 2015 and SFRH/BPD/85753/2012, respectively. KS and ZP are grateful for the working contract nanced by national funds under norma transitória D. L. no. 57/2016. Publisher Copyright: © The Royal Society of Chemistry.Aspergillus species are the primary cause of invasive aspergillosis, which afflicts hundreds of thousands of patients yearly, with high mortality rates. Amphotericin B is considered the gold standard in antifungal drug therapy, due to its broad-spectrum activity and rarely reported resistance. However, low solubility and permeability, as well as considerable toxicity, challenge its administration. Lipid formulations of amphotericin B have been used to promote its slow release and diminish toxicity, but these are expensive and adverse health effects of their prolonged use have been reported. In the past decades, great interest emerged on converting biologically active molecules into an ionic liquid form to overcome limitations such as low solubility or polymorphisms. In this study, we evaluated the biological activity of novel ionic liquid formulations where the cholinium, cetylpyridinium or trihexyltetradecylphosphonium cations were combined with an anionic form of amphotericin B. We observed that two formulations increased the antifungal activity of the drug, while maintaining its mode of action. Molecular dynamics simulations showed that higher biological activity was due to increased interaction of the ionic liquid with the fungal membrane ergosterol compared with amphotericin B alone. Increased cytotoxicity could also be observed, probably due to greater interaction of the cation with cholesterol, the main sterol in animal cells. Importantly, one formulation also displayed antibacterial activity (dual functionality), likely preserved from the cation. Collectively, the data set ground for the guided development of ionic liquid formulations that could improve the administration, efficacy and safety of antifungal drugs or even the exploitation of their dual functionality. This journal ispublishersversionpublishe