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Linking calcium signaling and mitochondrial function in fungal drug resistance
Monday, 2020/01/27 | 06:03:15

Paul Bowyer et al. 2020 (PNAS January 21, 2020 117 (3) 1254-1256)

 

The host range for Aspergillus fumigatus is wide, including mammals, aves, and insecta (stonebrood). This is linked to the significant adaptability of this important fungal pathogen. It is thermotolerant, able to grow up to 70 °C, and astonishingly also remains viable down to −20 °C (1). It is microaerophilic and a halophile; forms extensive biofilms, a problem for antifungal eradication in patients; and has >20 secondary metabolite biosynthetic clusters, some of the products of which have immunosuppressive and cytotoxic properties, such as gilotoxin. A. fumigatus also produces a large number of extracellular enzymes, many of which are allergenic, making this organism the only common human pathogen to also cause allergic disease. Further, its pathogenic capacity includes human lungs, airways, paranasal sinuses, and keratin-rich toenails, all in those without overt immune deficits. In immunocompromised people, invasion of lungs, skin, or paranasal sinuses is progressive and fatal, unless detected rapidly and optimally treated. A. fumigatus produces more allergenic proteins (n = ∼60) than any other living organism yet found. These allergens are produced in situ (usually in the airways) in those with asthma or cystic fibrosis, greatly worsening the patient’s condition, i.e., driving mild asthma to severe. All of these forms of aspergillosis are preferentially treated with oral triazole therapy, as the most efficacious and deliverable via intravenous and oral routes. With hundreds of thousands of people with life-threatening invasive aspergillosis and millions with chronic and allergic aspergillosis, our dependence on triazole therapy for better health is profound. Given the extraordinary range of biological attributes of A. fumigatus, it is no surprise that another adaptive mechanism of antifungal drug resistance has been described (2).

 

Resistance to azoles is increasing (3). In cases of invasive disease the majority of resistance is caused by mutation in the gene encoding the target enzyme, Cyp51A. Strains with one resistant allelic variant dominate in this setting and harbor both a tandem repeat in the cyp51A promoter (TR34) and a secondary nonsynonymous mutation within its coding sequence (L98H). These strains are often pan-azole resistant and acquired from the environment (4). Importantly, however, recent work (5) has shown that the most significant burden of disease caused by A. fumigatus relates to its chronic forms of infection that last many months or years. Patients with these conditions receive long-term therapy with azole drugs and resistance usually occurs through non–target-mediated mechanisms arising from mutations acquired during growth of the fungus within the lung under azole treatment pressure (6). One theory to account for this discrepancy in resistance profiles is that the stress responses used by the fungus to survive in the host allow first tolerance of low azole levels and then, after mutation, frank resistance to the drug.

 

A considerable body of evidence concerning mechanisms of non–target-mediated azole resistance has accumulated in recent years (Table 1). The observed mechanisms include mitochondrial respiratory function, calcium signaling, cell wall processes, and efflux pumps—a similar resistance landscape to that observed in yeast fungi such as Candida albicans. Several of these mechanisms are related to environmental stress conditions such as hypoxia and oxidative damage that may also lead directly to drug resistance phenotypes.

 

See more: https://www.pnas.org/content/117/3/1254

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