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Maciej Jaśkiewicz. Rozprawa Doktorska

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Maciej Jaśkiewicz. Rozprawa Doktorska Wydzia ł Farmaceutyczny z Oddzia łem Medycyny Laboratoryjnej ! Aktywno ść peptydów przeciwdrobnoustrojowych wobec biofilmu gronkowcowego w warunkach przep ływowych Maciej Ja śkiewicz Praca doktorska wykonana w Katedrze i Zak ładzie Chemii Nieorganicznej Gda ńskiego Uniwersytetu Medycznego Kierownik Katedry i Zak ładu Prof. dr hab. n. farm. Wojciech Kamysz Promotor Prof. dr hab. n. farm. Wojciech Kamysz Gda ńsk 2019 ! ! Cz ęść wyników zamieszczonych w niniejszej pracy otrzymana zosta ła w ramach projektu realizowanego ze środków Narodowego Centrum Nauki Nr 2011/03/B/NZ7/00548 ! ! Pragn ę z łożyć najserdeczniejsze podzi ękowania Promotorowi mojej pracy doktorskiej Panu Profesorowi Wojciechowi Kamyszowi Za pokazanie mi jak pasjonuj ąca mo że by ć Nauka ! ! ! Realizacja niniejszej pracy doktorskiej Nie oby łaby si ę bez wsparcia osób, Z którymi mia łem okazj ę wspó łpracowa ć. W tym miejscu Chcia łbym podzi ękowa ć Kole żankom i Kolegom Z Katedry i Zak ładu Chemii Nieorganicznej Dr n. med. Sylwii Bartoszewskiej Dr n. farm. Marcie Bauer Mgr. farm. Dariuszowi Markowi Mgr. in ż. Damianowi Neubauerowi Dr. n. chem. Karolowi Sikorze Ponadto serdecznie dzi ękuj ę Dr n. med. Izabeli B łażewicz oraz Pani Profesor Wioletcie Bara ńskiej-Rybak Z Katedry i Kliniki Dermatologii, Wenerologii i Alergologii Gda ńskiego Uniwersytetu Medycznego Za doskona łą wspó łprac ę i pomy śln ą realizacj ę Wszystkich celów naukowych ! ! ! SPIS TRE ŚCI WYKAZ SKRÓTÓW I SYMBOLI STOSOWANYCH W PRACY ....................................................... 8 SYMBOLE AMINOKWASÓW .............................................................................................................. 11 I. CZ ĘŚĆ TEORETYCZNA ............................................................................................................... 12 1. GRONKOWIEC Z ŁOCISTY ......................................................................................................... 12 1.1. ! INFEKCJE POWODOWANE PRZEZ S. AUREUS !""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!14 ! 1.1.1. Bakteriemia S. aureus ......................................................................................................... 15 1.1.2. Zaka żenia skóry i tkanek mi ękkich ...................................................................................... 17 1.1.3. Infekcyjne zapalenie wsierdzia ............................................................................................ 18 1.1.4. Zaka żenia kostno-stawowe ................................................................................................. 19 1.1.5. Zapalenie p łuc ..................................................................................................................... 20 1.1.6. Zaka żenia zwi ązane z protezami i biomateria łami ............................................................. 21 1.2. ! UDZIA Ł GRONKOWCÓW W ZAKA ŻENIACH SZPITALNYCH !""""""""""""""""""""""""""""""""""""""""""""""""""""!22 ! 1.3. ! CZYNNIKI WIRULENCJI ORAZ OPORNO ŚĆ NA ANTYBIOTYKI !"""""""""""""""""""""""""""""""""""""""""""""""""!24 ! 1.3.1. Czynniki adhezyjne ............................................................................................................. 24 1.3.2. Enzymy gronkowcowe ........................................................................................................ 24 1.3.3. Egzotoksyny ........................................................................................................................ 25 1.3.4. Oporno ść na antybiotyki .................................................................................................... 26 2. BIOFILM .......................................................................................................................................... 29 2.1. ! ETAPY TWORZENIA SI Ę BIOFILMU !""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!30 ! 3. TERAPIA INKFEKCJI GRONKOWCOWYCH .......................................................................... 32 3.1. ! ANTYBIOTYKOTERAPIA !""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!32 ! 4. PRZEP ŁYWOWY MODEL BADANIA BIOFILMU .................................................................. 38 4.1. ! PODSTAWOWE METODY OKRE ŚLANIA AKTYWNO ŚCI PRZECIWDROBNOUSTROJOWEJ !""""""""""!38 ! 4.2. ! METODY WYKORZYSTYWANE W OCENIE ELIMINACJI BIOFILMU !"""""""""""""""""""""""""""""""""""""""""""!39 ! 4.3. ! MODEL PRZEP ŁYWOWY !"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!41 ! ! ## ! 5. PEPTYDY PRZECIWDROBNOUSTROJOWE ........................................................................... 46 5.1. ! PODZIA Ł ZWI ĄZKÓW !"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!46 ! 5.2. ! MECHANIZM DZIA ŁANIA !""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!51 ! 5.3. ! SYNTETYCZNE PEPTYDY O PODWY ŻSZONEJ AKTYWNO ŚCI !""""""""""""""""""""""""""""""""""""""""""""""""""""!53 ! ! ! II. CEL PRACY .................................................................................................................................... 57 III. CZ ĘŚĆ DO ŚWIADCZALNA ........................................................................................................ 58 1. MATERIA ŁY I METODY .............................................................................................................. 58 1.1. ! APARATURA !"""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!58 ! 1.2. ! ODCZYNNIKI !""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""!60 ! 1.3. MATERIA ŁY LABORATORYJNE JEDNORAZOWEGO U ŻYTKU ................................................... 62 1.4. LINIE KOMÓRKOWE ORAZ SZCZEPY DROBNOUSTROJÓW ....................................................... 63 1.5. SYNTEZA ORAZ OCZYSZCZANIE PEPTYDÓW PRZECIWDROBNOUSTROJOWYCH .................... 65 1.6. WYMIANA ORAZ OZNACZANIE PRZECIWJONÓW W PEPTYDACH .......................................... 71 1) Otrzymywanie soli chlorkowych ............................................................................................. 71 2) Otrzymywanie soli octanowych .............................................................................................. 71 3) Oznaczanie zawarto ści przeciwjonów ..................................................................................... 72 1.7. OZNACZENIE ZAWARTO ŚCI PEPTYDU .................................................................................... 73 1.8. OCENA AKTYWNO ŚCI BADANYCH ZWI ĄZKÓW WOBEC SZCZEPÓW S. AUREUS .................... 74 1) Wyznaczanie minimalnego st ęż enia hamuj ącego wzrost ........................................................ 74 2) Wyznaczanie minimalnego st ęż enia eliminuj ącego biofilm .................................................... 75 3) Wyznaczanie minimalnego st ęż enia hamuj ącego rozwój biofilmu ......................................... 76 1.9. DODATKOWE BADANIA MIKROBIOLOGICZNE ........................................................................ 77 1) Badanie zjawiska narastania oporno ści ................................................................................... 77 2) Ocena depolaryzacji b łon ......................................................................................................... 77 1.10. WYZNACZANIE CYTOTOKSYCZNO ŚCI BADANYCH ZWI ĄZKÓW ............................................ 79 1) Ocena toksyczno ści wobec linii komórkowej keratynocytów ludzkich .................................... 79 2) Ocena aktywno ści hemolitycznej ............................................................................................. 80 1.11. UKŁADY PRZEP ŁYWOWE Z POLI (DIMETYLOSILOKSANU ) ....................................................... 81 1.12. OCENA AKTYWNO ŚCI PEPTYDÓW PRZECIWDROBNOUSTROJOWYCH WOBEC BIOFILMU GRONKOWCOWEGO W WARUNKACH PRZEP ŁYWOWYCH .................................................................... 83 1) Minimalne st ęż enia eliminuj ącego biofilm w przep ływie ....................................................... 84 2) Badanie zjawiska narastania oporno ści w przep ływowym modelu badawczym ..................... 85 3) Badanie wp ływu peptydów przeciwdrobnoustrojowych na formowanie si ę biofilmu w warunkach przep ływowych ............................................................................................................... 86 IV. OMÓWIENIE WYNIKÓW ORAZ DYSKUSJA ......................................................................... 87 1. OCENA WRA ŻLIWO ŚCI SZCZEPÓW KLINICZNYCH NA ANTYBIOTYKI I AMP S ....................... 87 2. PRZECIWGRONKOWCOWA AKTYWNO ŚĆ RETRO ANALOGÓW ............................................... 90 3. WPŁYW PRZECIWJONÓW NA AKTYWNO ŚĆ PRZECIWGRONKOWCOW Ą PEPTYDÓW .............. 93 4. PRZECIWGRONKOWCOWA AKTYWNO ŚĆ OMIGANANU I RETRO -OMIGANANU ................. 101 4.1. WYMIANA PRZECIWJONÓW .................................................................................................. 102 4.2. AKTYWNO ŚĆ RÓ ŻNYCH RODZAJÓW SOLI ............................................................................. 102 ! ! 4.3. OZNACZENIE ZAWARTO ŚCI PEPTYDÓW ............................................................................... 110 4.4. CYTOTOKSYCZNO ŚĆ RÓ ŻNYCH RODZAJÓW SOLI ................................................................
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