Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model.
(2024) In Antimicrobial Agents and Chemotherapy 68(1).- Abstract
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... (More)The newly emerged pathogen,
(Less)
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-
sn-glycero-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.
- author
- organization
- publishing date
- 2024-01-10
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Humans, Antifungal Agents/pharmacology, Candida, Candida auris, Liposomes, Microbial Sensitivity Tests, Biofilms
- in
- Antimicrobial Agents and Chemotherapy
- volume
- 68
- issue
- 1
- article number
- e00955-23
- publisher
- American Society for Microbiology
- external identifiers
-
- scopus:85183950135
- pmid:38092678
- ISSN
- 1098-6596
- DOI
- 10.1128/aac.00955-23
- language
- English
- LU publication?
- yes
- id
- ebf6bced-6080-4778-af42-cb7de8238cf0
- date added to LUP
- 2024-02-02 10:52:45
- date last changed
- 2024-04-26 16:59:31
@article{ebf6bced-6080-4778-af42-cb7de8238cf0,
abstract = {{<p>The newly emerged pathogen, <br>
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 <br>
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 <br>
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 <br>
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 <br>
N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-<br>
sn-glycero-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 <br>
C. auris in <br>
in vitro biofilms and <br>
ex vivo skin colonization models. These initial results suggest that molecules like PQA-Az-13 warrant further study and development.<br>
</p>}},
author = {{Jaromin, Anna and Zarnowski, Robert and Markowski, Adam and Zagórska, Agnieszka and Johnson, Chad J and Etezadi, Haniyeh and Kihara, Shinji and Mota-Santiago, Pablo and Nett, Jeniel E and Boyd, Ben J and Andes, David R}},
issn = {{1098-6596}},
keywords = {{Humans; Antifungal Agents/pharmacology; Candida; Candida auris; Liposomes; Microbial Sensitivity Tests; Biofilms}},
language = {{eng}},
month = {{01}},
number = {{1}},
publisher = {{American Society for Microbiology}},
series = {{Antimicrobial Agents and Chemotherapy}},
title = {{Liposomal formulation of a new antifungal hybrid compound provides protection against <i>Candida auris</i> in the <i>ex vivo</i> skin colonization model.}},
url = {{http://dx.doi.org/10.1128/aac.00955-23}},
doi = {{10.1128/aac.00955-23}},
volume = {{68}},
year = {{2024}},
}