A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1

Jeffrey M. Rybak, Jinhong Xie, Adela Martin-Vicente, Xabier Guruceaga, Harrison I. Thorn, Ashley V. Nywening, Wenbo Ge, Ana C. O. Souza, Amol C. Shetty, Carrie McCracken, Vincent M. Bruno, Josie E. Parker, Steven L. Kelly, Hannah M. Snell, Christina A. Cuomo, P. David Rogers and Jarrod R. Fortwendel ()
Additional contact information
Jeffrey M. Rybak: St. Jude Children’s Research Hospital
Jinhong Xie: University of Tennessee Health Science Center
Adela Martin-Vicente: University of Tennessee Health Science Center
Xabier Guruceaga: University of Tennessee Health Science Center
Harrison I. Thorn: University of Tennessee Health Science Center
Ashley V. Nywening: University of Tennessee Health Science Center
Wenbo Ge: University of Tennessee Health Science Center
Ana C. O. Souza: St. Jude Children’s Research Hospital
Amol C. Shetty: University of Maryland School of Medicine
Carrie McCracken: University of Maryland School of Medicine
Vincent M. Bruno: University of Maryland School of Medicine
Josie E. Parker: Cardiff University
Steven L. Kelly: Swansea University Medical School
Hannah M. Snell: Broad Institute of MIT and Harvard
Christina A. Cuomo: Broad Institute of MIT and Harvard
P. David Rogers: St. Jude Children’s Research Hospital
Jarrod R. Fortwendel: University of Tennessee Health Science Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.

Date: 2024
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DOI: 10.1038/s41467-024-48029-2

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