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

2024
journal article
article
21
dc.abstract.enThe 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-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.
dc.affiliationWydział Farmaceutyczny : Zakład Chemii Lekówpl
dc.cm.date2024-01-10T23:16:36Z
dc.cm.id114146pl
dc.cm.idOmegaUJCMc7c7d45f4c61430bb42e8a99d7b01d45pl
dc.contributor.authorJaromin, Annapl
dc.contributor.authorRobert, Zarnowskipl
dc.contributor.authorAdam, Markowskipl
dc.contributor.authorZagórska, Agnieszka - 133872 pl
dc.contributor.authorJ., Johnson Chadpl
dc.contributor.authorHaniyeh, Etezadipl
dc.contributor.authorShinji, Kiharapl
dc.contributor.authorPablo, Mota-Santiagopl
dc.contributor.authorE., Nett Jenielpl
dc.contributor.authorJ., Boyd Benpl
dc.contributor.authorR., Andes Davidpl
dc.date.accession2024-01-10pl
dc.date.accessioned2024-01-10T23:16:36Z
dc.date.available2024-01-10T23:16:36Z
dc.date.issued2024pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.number1pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume68pl
dc.identifier.articleide00955-23pl
dc.identifier.doi10.1128/aac.00955-23pl
dc.identifier.eissn1098-6596pl
dc.identifier.issn0066-4804pl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/325301
dc.identifier.weblinkhttps://journals.asm.org/doi/10.1128/aac.00955-23pl
dc.languageengpl
dc.language.containerengpl
dc.pbn.affiliationDziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licenceCC-BY
dc.rights.simpleviewWolny dostęp
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.typeOtwarte czasopismo
dc.source.integratorfalse
dc.subject.encandida auris
dc.subject.enbiofilm
dc.subject.enantifungal
dc.subject.enproteomics
dc.subject.enliposomes
dc.subject.enfungal skin infection
dc.subtypeArticlepl
dc.titleLiposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization modelpl
dc.title.journalAntimicrobial Agents and Chemotherapypl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.en
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-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.
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Chemii Leków
dc.cm.date
2024-01-10T23:16:36Z
dc.cm.idpl
114146
dc.cm.idOmegapl
UJCMc7c7d45f4c61430bb42e8a99d7b01d45
dc.contributor.authorpl
Jaromin, Anna
dc.contributor.authorpl
Robert, Zarnowski
dc.contributor.authorpl
Adam, Markowski
dc.contributor.authorpl
Zagórska, Agnieszka - 133872
dc.contributor.authorpl
J., Johnson Chad
dc.contributor.authorpl
Haniyeh, Etezadi
dc.contributor.authorpl
Shinji, Kihara
dc.contributor.authorpl
Pablo, Mota-Santiago
dc.contributor.authorpl
E., Nett Jeniel
dc.contributor.authorpl
J., Boyd Ben
dc.contributor.authorpl
R., Andes David
dc.date.accessionpl
2024-01-10
dc.date.accessioned
2024-01-10T23:16:36Z
dc.date.available
2024-01-10T23:16:36Z
dc.date.issuedpl
2024
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.numberpl
1
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
68
dc.identifier.articleidpl
e00955-23
dc.identifier.doipl
10.1128/aac.00955-23
dc.identifier.eissnpl
1098-6596
dc.identifier.issnpl
0066-4804
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/325301
dc.identifier.weblinkpl
https://journals.asm.org/doi/10.1128/aac.00955-23
dc.languagepl
eng
dc.language.containerpl
eng
dc.pbn.affiliation
Dziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.rights
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.simpleview
Wolny dostęp
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
Otwarte czasopismo
dc.source.integrator
false
dc.subject.en
candida auris
dc.subject.en
biofilm
dc.subject.en
antifungal
dc.subject.en
proteomics
dc.subject.en
liposomes
dc.subject.en
fungal skin infection
dc.subtypepl
Article
dc.titlepl
Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model
dc.title.journalpl
Antimicrobial Agents and Chemotherapy
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

* The migration of download and view statistics prior to the date of April 8, 2024 is in progress.

Views
11
Views per month
Views per city
Krakow
3
Singapore
1
Downloads
zagorska_et-al_liposomal_formulation_of_a_new_antifungal_hybrid_2024.pdf
151