Ariani, Novida (2018) Sinergi Kurkumin Dengan Flukonazole Menghambat Candida Albicans Strain Resisten Flukonazole Dari Isolate Orofaring Pasien Hiv Melalui Ekspresi Cdr1p, Hat-Rtt109, Metilasi Cdr1 & Rtt109. Doktor thesis, Universitas Brawijaya.
Abstract
Insidensi infeksi fungal saat ini meningkat signifikan dan menyebabkan peningkatan morbiditas dan mortalitas. Pada dekade terakhir terjadi peningkatan signifikan resistensi antifungal melawan C. albicans. Resistensi ini memiliki implikasi penting bagi morbiditas, mortalitas dan bia ya layanan kesehatan masyarakat. Tantangan mengatasi resistensi semakin berat karena penggunaan agen antifungal seperti azole yang masif terbentur oleh toksisitasnya yang tinggi. Suatu studi menunjukkan bahwa resistensi azole terjadi hingga sepertiga isolat C. albicans oral yang diperoleh dari pasien positif-HIV. Mekanisme resistensi antifungal antara lain : 1) Perubahan genetik membran lipid C. albicans yaitu ergosterol, dan 2) Perubahan pada membran drug efflux transporter, antara lain: kelas ABC (ATP binding cassette) seperti Cdrp1 (dikodekan oleh CDR1), Cdrp2 (dikodekan oleh CDR2), dan kelas MFS ( Major Fascilitator Superfamily). Bila terjadi perubahan mekanisme resistensi di atas, antifungal tidak dapat lagi masuk dan bekerja mengganggu integritas membran Candida. C. albicans akan tetap bertahan hidup dan tetap memberikan gejala infeksi pada host. Faktor epigenetik merupakan faktor di luar gen yang dapat mempengaruhi ekspresi protein drug efflux transporter. Faktor epigenetik meliputi: 1) Asetilasi histon, dan 2) Metilasi DNA. HAT (Histone Acetyl Transferase) mengkatalisa asetilasi histon. Asetilasi histone menyebabkan ikatan histon dengan nukleosom menjadi longgar dan proses ini akan memulai transkripsi gen resistensi seperti CDR1. Aktivasi CDR1 meningkatkan drug efflux transporter seperti Cdrp1 yang kemudian menyebabkan Candida resisten. Baru- baru ini ditemukan bahwa suatu enzim Histone Acetyl Transferase (HAT) Rtt109, enzim yang hanya ada dalam kingdom fungal, diperlukan untuk patogenisitas fungal. Tanpa Rtt109, fungal hipersensitif terhadap efek viii genotoksik dari reactive oxygen species (ROS) dan gangguan respon stress drug efflux transporter. Inhibisi HAT Rtt109 sangat mungkin mempengaruhi ekspresi Cdrp1 sehingga akan menurunkan resistensi antifungal.
English Abstract
Fungal infection incident was rising significantly and causing morbidity and mortality increase. During last decade there was significant increase in antifungal resistance against C. albicans. This resistance carry the important implication for morbidity, mortality and community health service cost. Challenge to face this resistance was higher due to the use of antifungal agent such as azole which still limited by its high level of toxicity. A study showed that azole resistance occur in almost one third of oral C. albicans isolates collected from HIV-positive patients. Antifungal resistance mechanisme involving: 1) Genetic change in C. albicans lipid membrane that is ergosterol, and 2) Changes in drug efflux transporter membranes such as: ABC class (ATP binding cassette) like Cdrp1 (code by CDR1), Cdrp2 (code by CDR2) and MFS class (Major Facilitator Superfamily). If the above changes occurs, antifungal could no longer enter and disturb the integrity of Candida membranes. C. albicans would still survive and continuously gave infection symptoms toward its host Epigenetic factor is the factor outside of the genes that could affect protein expression of drug efflux transporter. Epigenetic factors includes: 1) Histone acetylation and 2) DNA methylation. HAT (Histone Acetyl Transferase) would catalyze histone acetylation. Histone acetylation would loosened the binding between histone and nucleosome which would trigger then the resistance gene transcription such as CDR1. CDR1 activation would improve drug efflux transporter such as Cdrp1 and would cause resistant Candida. Lately, it was discovered that a Histone Acetyl Transferase (HAT) enzyme, Rtt109, which only exist in fungal kingdom, was needed for fungal pathogenicity. Without Rtt109, fungal would be hypersensitive toward genotoxic effect from reactive oxygen species (ROS) and stress response disturbance of drug efflux transporter. Inhibition of HAT Rtt109 xii would probably influence Cdrp1 expression and thus lowering antifungal resistance.
Other obstract
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| Item Type: | Thesis (Doktor) |
|---|---|
| Identification Number: | DES/616.979 2/ARI/s/2018/061804280 |
| Subjects: | 600 Technology (Applied sciences) > 616 Diseases > 616.9 Other disease > 616.97 Diseases of immune system > 616.979 Immune deficiency diseases > 616.979 2 Acquired immune deficiency syndrome (AIDS) |
| Divisions: | S2/S3 > Doktor Ilmu Kedokteran, Fakultas Kedokteran |
| Depositing User: | Endang Susworini |
| Date Deposited: | 22 Sep 2022 03:23 |
| Last Modified: | 22 Sep 2022 03:23 |
| URI: | http://repository.ub.ac.id/id/eprint/194585 |
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