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Azole resistance in Aspergillus fumigatus: genetic background and mechanisms of spread in the Czech Republic
Holíková, Kristýna ; Hubka, Vít (advisor) ; Chrenková, Vanda (referee)
Aspergillus fumigatus is a widespread saprophytic fungus. As an opportunistic pathogen it can also cause aspergillosis, which can manifest itself as a life-threatening infection in immunocompromised patients. Azole derivatives constitute first-line therapy of aspergillosis, but the increase worldwide of azole-resistant A. fumigatus strains represents a serious clinical problem. So far most of the molecular mechanisms causing azole resistance are dependent on the cyp51A gene. Studies of the last decade have shown that primarily because of the use of azole fungicides in agriculture, azole-resistant strains of A. fumigatus are selected in the environment. This subsequently complicates the treatment of patients with aspergillosis, and the incidence of infections unresponsive to treatment with azole antifungals increases. Increasing incidence of azole antifungals-resistant infections has become a growing concern: yet the prevalence of azole resistance has not yet been assessed in Czech Republic. Therefore, the first objective of this thesis was to determine Czech Republic's prevalence of azole resistance in clinical strains of A. fumigatus. Those findings permitted the observation of the molecular-genetic mechanisms of this resistance. Second aim was to study environmental prevalence of azole resistance...
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Genetic background and spread of azole resistance in Aspergillus fumigatus
Holíková, Kristýna ; Hubka, Vít (advisor) ; Lysková, Pavlína (referee)
Aspergillus is a globally widespread saprophytic filamentous genus of fungi, including opportunistic pathogenic species that cause a disease called aspergillosis. Azole derivatives have an irreplaceable role in the treatment of aspergillosis. These drugs inhibit the biosynthetic pathway of ergosterol. That leads to disruption of the fungal plasma membrane. However, nowadays, the rate of occurrence of azole-resistant fungi is rapidly increasing, which also increases the mortality of the patients. The aim of this bachelor thesis is to summarize the current knowledge associated with azole resistance with focus on its genetic background and global distribution. The main emphasis is given on the species Aspergillus fumigatus which is the most common agent of aspergillosis. Resistance to azole derivatives arises from prolonged fungi exposure to azole drugs or fungicides. The most common origin of azole resistance relates to the use of azole fungicides in agriculture. There are several ways how the resistance works. Most of them, however, relate to changes in the cyp51A gene, which is affected by azoles, and its promoter, with the most frequent mutation being TR34/L98H. The most common mechanism of the resistance that is not associated with changes in the cyp51A gene is increased expression of efflux...
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