Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model
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Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model. / Jaromin, Anna; Zarnowski, Robert; Markowski, Adam; Zagórska, Agnieszka; Johnson, Chad J.; Etezadi, Haniyeh; Kihara, Shinji; Mota-Santiago, Pablo; Nett, Jeniel E.; Boyd, Ben J.; Andes, David R.
In: Antimicrobial Agents and Chemotherapy, Vol. 68, No. 1, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Liposomal formulation of a new antifungal hybrid compound provides protection against Candida auris in the ex vivo skin colonization model
AU - Jaromin, Anna
AU - Zarnowski, Robert
AU - Markowski, Adam
AU - Zagórska, Agnieszka
AU - Johnson, Chad J.
AU - Etezadi, Haniyeh
AU - Kihara, Shinji
AU - Mota-Santiago, Pablo
AU - Nett, Jeniel E.
AU - Boyd, Ben J.
AU - Andes, David R.
N1 - Publisher Copyright: © 2023 Jaromin et al.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - antifungal
KW - biofilm
KW - Candida auris
KW - fungal skin infection
KW - liposomes
KW - proteomics
U2 - 10.1128/aac.00955-23
DO - 10.1128/aac.00955-23
M3 - Journal article
C2 - 38092678
AN - SCOPUS:85183950135
VL - 68
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 1
ER -
ID: 382495292