Enhanced antifungal activity of posaconazole against Candida auris by HIV protease inhibitors, atazanavir and saquinavir.

Autor: Elgammal Y; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1410 Prices Fork Rd, Blacksburg, VA, 24061, USA.; Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA., Salama EA; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1410 Prices Fork Rd, Blacksburg, VA, 24061, USA.; Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA., Seleem MN; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1410 Prices Fork Rd, Blacksburg, VA, 24061, USA. seleem@vt.edu.; Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA. seleem@vt.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jan 18; Vol. 14 (1), pp. 1571. Date of Electronic Publication: 2024 Jan 18.
DOI: 10.1038/s41598-024-52012-8
Abstrakt: The increasing incidence and dissemination of multidrug-resistant Candida auris represents a serious global threat. The emergence of pan-resistant C. auris exhibiting resistance to all three classes of antifungals magnifies the need for novel therapeutic interventions. We identified that two HIV protease inhibitors, atazanavir and saquinavir, in combination with posaconazole exhibited potent activity against C. auris in vitro and in vivo. Both atazanavir and saquinavir exhibited a remarkable synergistic activity with posaconazole against all tested C. auris isolates and other medically important Candida species. In a time-kill assay, both drugs restored the fungistatic activity of posaconazole, resulting in reduction of 5 and 5.6 log 10 , respectively. Furthermore, in contrast to the individual drugs, the two combinations effectively inhibited the biofilm formation of C. auris by 66.2 and 81.2%, respectively. Finally, the efficacy of the two combinations were tested in a mouse model of C. auris infection. The atazanavir/posaconazole and saquinavir/posaconazole combinations significantly reduced the C. auris burden in mice kidneys by 2.04- (99.1%) and 1.44-log 10 (96.4%) colony forming unit, respectively. Altogether, these results suggest that the combination of posaconazole with the HIV protease inhibitors warrants further investigation as a new therapeutic regimen for the treatment of C. auris infections.
(© 2024. The Author(s).)
Databáze: MEDLINE
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