Guruceaga Sierra, Xabier

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https://academica-e.unavarra.es/handle/2454/52637

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Guruceaga Sierra

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Xabier

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Agronomía, Biotecnología y Alimentación

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0000-0003-3258-2482

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1174909

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811191

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    PublicationOpen Access
    A secondary mechanism of action for triazole antifungals in aspergillus fumigatus mediated by hmg1
    (Springer Nature, 2024-04-29) Rybak, Jeffrey M.; Xie, Jinhong; Martín-Vicente, Adela; Guruceaga Sierra, Xabier; Thorn, Harrison I.; Nywening, Ashley V.; Ge, Wenbo; Souza, Ana Camila Oliveira; Shetty, Amol C.; McCracken, Carrie; Bruno, Vincent M.; Parker, Josie E.; Kelly, Steven L.; Snell, Hannah M.; Cuomo, Christina A.; Rogers, P. David; Fortwendel, Jarrod R.; Agronomía, Biotecnología y Alimentación; Agronomia, Bioteknologia eta Elikadura
    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-¿-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.
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    PublicationOpen Access
    The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of aspergillus species.
    (Springer Nature, 2024-05-20) Xie, Jinhong; Rybak, Jeffrey M.; Martín-Vicente, Adela; Guruceaga Sierra, Xabier; Thorn, Harrison I.; Nywening, Ashley V.; Ge, Wenbo; Parker, Josie E.; Kelly, Steven L.; Rogers, P. David; Fortwendel, Jarrod R.; Agronomía, Biotecnología y Alimentación; Agronomia, Bioteknologia eta Elikadura
    Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.
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    PublicationOpen Access
    A conserved fungal morphogenetic kinase regulates pathogenic growth in response to carbon source diversity
    (Springer Nature, 2024-12-17) Martín-Vicente, Adela; Souza, Ana Camila Oliveira; Guruceaga Sierra, Xabier; Thorn, Harrison I.; Xie, Jinhong; Nywening, Ashley V.; Ge, Wenbo; Fortwendel, Jarrod R.; Agronomía, Biotecnología y Alimentación; Agronomia, Bioteknologia eta Elikadura
    Fungal pathogens must exhibit strong nutritional plasticity, effectively sensing and utilizing diverse nutrients to support virulence. How the signals generated by nutritional sensing are efficiently translated to the morphogenetic machinery for optimal growth and support of virulence remains incompletely understood. Here, we show that the conserved morphogenesis-related kinase, CotA, imparts isoform-specific control over Aspergillus fumigatus invasive growth in host-mimicking environments and during infection. CotA-mediated invasive growth is responsive to exogenous carbon source quality, with only preferred carbon sources supporting hyphal morphogenesis in a mutant lacking one of two identified protein isoforms. Strikingly, we find that the CotA protein does not regulate, nor is cotA gene expression regulated by, the carbon catabolite repression system. Instead, we show that CotA partially mediates invasive growth in specific carbon sources and virulence through the conserved downstream effector and translational repressor, SsdA. Therefore, A. fumigatus CotA accomplishes its conserved morphogenetic functions to drive pathogenic growth by translating host-relevant carbon source quality signals into morphogenetic outputs for efficient tissue invasive growth.