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CHEMISTRY OF SPECIALIZED METABOLITES FROM HAWAIIAN FUNGI AND THEIR ANTIBACTERIAL AND ANTIPLATELET POTENTIALS
|ZAMAN_hilo.hawaii_1418E_10218.pdf||13.75 MB||Adobe PDF||View/Open|
|Dissertation_SD_Zaman_For Library_04.13.2022.pdf||52.2 MB||Adobe PDF||View/Open|
File under embargo until 2023-05-26
|dc.contributor.author||ZAMAN, KH AHAMMAD UZ|
|dc.subject||Protein synthesis inhibitor|
|dc.title||CHEMISTRY OF SPECIALIZED METABOLITES FROM HAWAIIAN FUNGI AND THEIR ANTIBACTERIAL AND ANTIPLATELET POTENTIALS|
|dcterms.abstract||For centuries, natural products have been and still is considered as the major source of new drug molecules, as about 50% of the approved drug during the last four decades are natural products, natural product derivatives, or synthetic compounds that are inspired by natural product structures.1 Moreover, the alarming rate of microbial resistance to existing drugs necessitates the development of new antibiotics from relatively new and underexplored sources, e.g., fungi. In 2018, according to the states of the world's fungi, only 7% of the world's fungal species were characterized, which means the other 93% of the fungi kingdom remain to be discovered. Despite the mid-oceanic location of Hawaii, it provides diverse ecosystems, such as tropical rain forests, marine environments, and coastlines. However, due to the lack of research on Hawaiian fungi, especially from offshore marine species and soils of high mountains and volcanoes, there is a huge scope to explore them for their biological potential. The present study describes our continuous efforts to interrogate Hawaii-derived terrestrial and marine fungi, for their biological potentials. The first specific aim of the current project was to isolate and identify pure fungal isolates from very selective locations in the Hawaiian Islands. After detailed antibacterial and antiproliferative assays, five fungal strains from five different sources, such as Aspergillus terreus FS107, Fusarium sp. FM701, Xylaria sp. FM1005, Fusarium graminearum FM1010 and Trichoderma sp. FM652, were identified as active strains among many other isolated fungi. The second specific aim of the study was to isolate and identify compounds from different Hawaiian fungi. A significant number (34) of previously undescribed specialized metabolites such as analogs of fusidic acid, tryptoquivaline, fusaric acid, fumagillin, tyrosine, etc., were isolated from different Aspergillus, Fusarium, Xylaria, and Trichoderma species. The structures of these compounds were elucidated by spectroscopic interpretation, including HR-ESIMS and NMR, electronic circular dichroism (ECD) analysis and chemical reactions.Four previously undescribed fusidic acid analogs maunakeanolic acids A-C (1.11.2, 1.4), and 6-deacetyl-1,2-dihydrohelvolic acid (1.3), one fumagillin derivative maunakeanolin (1.8), and two tryptoquivaline analogs tryptoquivalines W-X (1.121.13) were isolated from Mauna kea soil-derived fungus Aspergillus terreus FS107. Figure A. Graphical abstract of compounds from Aspergillus terreus. From two marine Fusarium (Fusarium sp. FM701 and Fusarium graminearum FM1010) species, nine previously unknown fungal polyketides, kaneoheoic acids AI (2.12.6 and 5.35.5) and two unique fusaric acid derivatives, fusariumic acids A-B (2.102.11), two undescribed diketopiperazines, gramipiperazines A-B (5.15.2), and one new isochromanone, along with eight other related compounds were isolated. Furthermore, five new tyrosine derivatives, sinuxylamides A-E (3.13.5), one new phenylacetic acid derivative, two new quinazolinone analogues, one new naphthalenedicarboxylic acid, and one new 3,4-dihydroisocoumarin derivative, were isolated from the marine fungus Xylaria sp. FM1005, which was isolated from Sinularia densa (leather coral) collected in the offshore region of the Big Island, Hawaii. Finally, two new sorbicillinoid derivatives, 2,3-dihydro-2-hydroxy vertinolides (4.1) and (-)-trichodermatone (4.2), together with ten other related compounds were isolated from a Hawaiian marine fungal strain Trichoderma sp. FM652. Figure B. Graphical abstract of compounds from Xylaria sp. and their activity. The third specific aim of the study was to investigate the biological potential of the newly isolated compounds, especially their antibacterial activities. Fusidic acid derivatives from Aspergillus terreus exhibited promising antibacterial activities against both Gram-positive and Gram-negative bacteria. Although, polyketides from both Fusarium species did not show any activity against pathogenic bacteria, the majority of them exhibited significant antibacterial activity against Staphylococcus aureus, methicillin resistant Staphylococcus aureus and Bacillus subtilis, in the range of 10–80 μg/mL in the presence of either antibiotic chloramphenicol (half of the MIC, 1 μg/mL) or an established antibiotic adjuvant disulfiram (6 μg/mL). Moreover, these antibiotic adjuvants also increased the antibacterial activities of fusidic acid derivatives against Gram-positive bacteria by two to three folds. Moreover, this study unexpectedly discovered new tyrosine derivatives, sinuxylamides A-B, which displayed promising antiplatelet activities. The fourth specific aim of the study was to determine the underlying mechanism of the biological activities, such as antibacterial and antiplatelet activities of the newly isolated compounds. The fusidic acid analogs, maunakeanolic acids A-C (1.11.2 and 1.4), 6-deacetyl-1,2-dihydrohelvolic acid (1.3), helvolic acid (1.5), 1,2-dehydrohelvolic acid (1.6) and helvolinic acid (1.7), strongly bound to the elongation factor G (EF-G)-GDP complex of ribosome and inhibited both peptide translocation and ribosome disassembly, resulting in inhibition of protein synthesis. Although all of them bound with both S. aureus and E. coli ribosomal EF-G-GDP complex, maunakeanolic acids A-C, 6-deacetyl-1,2-dihydrohelvolic acid, and helvolinic acid showed stronger binding affinity to S. aureus EF-G-GDP, whereas helvolic acid and 1,2-dehydrohelvolic acid showed stronger affinity to E. coli EF-G-GDP. Interestingly, helvolinic acid has better effect to form complex with S. aureus EF-G-GDP than the FDA-approved drug fusidic acid (parent molecule of the newly isolated triterpenoids). Due to their structure similarity to the FDA-approved antiplatelet drug tirofiban, sinuxylamides A-E (3.13.5) were investigated to find out the mechanism for their antithrombotic activities. Like tirofiban, sinuxylamides A and B strongly inhibited the binding of fibrinogen to purified integrin IIIb/IIa in a dose-dependent manner with the IC50 values of 0.89 and 0.61 μM, respectively. Collectively, the results of this study suggest that Hawaiian fungi have great potential as new source of promising lead compounds with excellent biological activities. In addition, the mechanism of action study revealed that fusidic acid analogs and tyrosine derivatives worked by the same mechanism as the positive controls, fusidic acid and tirofiban, respectively. These findings lead to further investigations of the compounds that may lead to the new drug development.|
|dcterms.publisher||University of Hawaii at Hilo|
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