Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model

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The newly emerged pathogen, Candida auris, presents a serious threat to public health worldwide. This multidrug-resistant yeast often colonizes and persists on the skin of patients, can easily spread from person to person, and can cause life-threatening systemic infections. New antifungal therapies are therefore urgently needed to limit and control both superficial and systemic C. auris infections. In this study, we designed a novel antifungal agent, PQA-Az-13, that contains a combination of indazole, pyrrolidine, and arylpiperazine scaffolds substituted with a trifluoromethyl moiety. PQA-Az-13 demonstrated antifungal activity against biofilms of a set of 10 different C. auris clinical isolates, representing all four geographical clades distinguished within this species. This compound showed strong activity, with MIC values between 0.67 and 1.25 µg/mL. Cellular proteomics indicated that PQA-Az-13 partially or completely inhibited numerous enzymatic proteins in C. auris biofilms, particularly those involved in both amino acid biosynthesis and metabolism processes, as well as in general energy-producing processes. Due to its hydrophobic nature and limited aqueous solubility, PQA-Az-13 was encapsulated in cationic liposomes composed of soybean phosphatidylcholine (SPC), 1,2-dioleoyloxy-3-trimethylammonium-propane chloride (DOTAP), and N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-snglycero-3-phosphoethanolamine, sodium salt (DSPE-PEG 2000), and characterized by biophysical and spectral techniques. These PQA-Az-13-loaded liposomes displayed a mean size of 76.4 nm, a positive charge of +45.0 mV, a high encapsulation efficiency of 97.2%, excellent stability, and no toxicity to normal human dermal fibroblasts. PQA-Az-13 liposomes demonstrated enhanced antifungal activity levels against both C. auris in in vitro biofilms and ex vivo skin colonization models. These initial results suggest that molecules like PQA-Az-13 warrant further study and development.

OriginalsprogEngelsk
TidsskriftAntimicrobial Agents and Chemotherapy
Vol/bind68
Udgave nummer1
Antal sider18
ISSN0066-4804
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
The authors would like to acknowledge Jennifer J. Meudt and Dhanansayan Shanmuganayagam for the provision of porcine skin. Additionally, we acknowledge the MAX IV Laboratory, for the time on the CoSAXS Beamline, under Proposal 20211082. Research conducted at MAX IV, a Swedish national user facility, is supported by the Swedish Research council, under contract 2018–07152, the Swedish Governmental Agency for Innovation Systems, under contract 2018–04969, and Formas, under contract 2019– 02496. This work from the use of the SasView application, originally developed under NSF award DMR-0520547. SasView contains code developed with funding from the European Union’s Horizon 2020 research and innovation program, under the SINE2020 project, grant agreement No. 654000.

Funding Information:
Publication of this article was supported by the Excellence Initiative—Research University program for the University of Wrocław. The project is by the Polish National Agency for Academic Exchange (PPN/BIL/2018/2/00108) and the Italian Ministry of Foreign and International Cooperation “Executive Programme for and Technological Cooperation between the Italian Republic and the Republic of Poland” (PO19MO10). This study was partly supported by NIH/NIAID R01AI073289. B.B., S.K., and H.E. are funded by the Novo Nordisk Foundation under the Novo Nordisk Foundation Laureate Research Fellowship scheme.

Publisher Copyright:
© 2023 Jaromin et al.

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