VCOM Research Day Program Book 2023

Graduate Student Research Biomedical

15 Re-Sensitization of A. Fumigatus Through the Addition of HIV Protease Inhibitors

Nicholas D. Burns; Ehab Salama; Mohamed Seleem

Virginia Tech

antifungal activity of current therapies. We identified the HIV-protease inhibitor, lopinavir (LPV), as a viable and effective co-drug able for itraconazole and posaconazole against A. fumigatus and others. Here, we investigate the interactions between LPV and different azole drugs, effective or not (itraconazole, posaconazole or voriconazole respectively) against a plethora of A. fumigatus clinically important isolates. Lopinavir displayed a synergistic relationship with itraconazole against 16 isolates (ƩFICI range of 0.188-0.375), while an indifferent effect was observed against five isolates (ƩFICI ranged from 0.53 to 1.125). Most notably, lopinavir in combination with posaconazole, demonstrated effective antifungal properties against 18 isolates (ƩFICI ranged from 0.091 to 0.188), while an indifference effect observed

only against three azole-resistant isolates (ƩFICI ranged from 0.53 to 0.62). In addition, LPV was able to re-sensitize azole-resistant A. fumigatus strains, such as CDC 731 and CDC 733, to the antifungal activity of azoles. These results generate a new avenue of research and clinical regimens that can re sensitize or drastically reduce the azole burden needed to successfully treat Aspergillus fumigatus infections.

Aspergillus fumigatus globally contributes to than 300,000 infections. Invasive pulmonary aspergillosis predates immunosuppressed patients directly causing life-threatening fungal infection, with mortality ranging from 70-90%. Triazoles, including voriconazole, itraconazole, posaconazole, are front line therapies, with few drugs being developed, for immediate treatment or prophylaxis of infections due to Aspergillus sp ., increased mutations. Most concerning is the increasing amount of azole-resistant strains of A. fumigatus this has been steadily gaining attention due to treatment failure and high mortality. In recognition of this threat, the WHO has listed them as a critical priority group. Therefore, we are searching for an adjuvant/complementary agent to re-sensitize azole-resistant A. fumigatus to the

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