The repurposing of chemical compounds as anti-Cryptococcus drugs
| dc.contributor.advisor | Sebolai, O.M. | |
| dc.contributor.advisor | Pohl, C. H. | |
| dc.contributor.author | Ogundeji, Adepemi Olawunmi | |
| dc.date.accessioned | 2017-07-26T06:33:36Z | |
| dc.date.available | 2017-07-26T06:33:36Z | |
| dc.date.issued | 2017-01 | |
| dc.description.abstract | English: The manifestation of disseminated cryptococcal infection in HIV-infected individual is a life-threatening infection, with 70% mortality rate in sub-Saharan Africa. People are dying because of the complications around the management. Thus, there is a need for alternative drugs for better management of HIV-associated cryptococcal infection. This thesis successfully demonstrated in vitro anti-cryptococcus activity of: 1) anti-inflammatory drugs (aspirin and ibuprofen), 2) aspirinate-metal complex (CAS), and 3) anti-psychotic drugs (quetiapine and olanzapine). In this thesis, EUCAST guidelines were followed closely and this provides a sense of effectiveness, which is very important for improving patient outcomes. Chapter 2 focused on repurposing aspirin and ibuprofen as alternative anti-cryptococcal drugs. The major findings from this part of the thesis show that, all the tested fungal strains revealed a dose dependent response profile towards aspirin and ibuprofen. Compared to aspirin, ibuprofen exerts greater antimicrobial action. More importantly, the MICs of both drugs did not negatively affect the functioning of macrophages - rather they enhanced the phagocytic capability of macrophages to internalize more cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B at lower concentrations than individual concentrations tested. Our findings revealed the mode of action employed by aspirin and ibuprofen which is via oxidative damage. Chapter 3 focused on a derivative of aspirin viz. copper acyl salicylate (CAS). CAS possess anti-fungal activity against cryptococcal cells and acted in synergy with fluconazole and amphotericin B at lower concentrations than their individual concentrations tested. CAS also kills cells via reactive oxygen species (ROS)-mediated membrane damage. The effect of CAS did not negatively affect macrophages but rather enhance their phagocytic function. Comparing with aspirin, CAS led to more growth reduction and showed less toxicity. Today, one of the main challenges in the management of disseminated cryptococcal infections is the secondary complications such as psychosis. Therefore, chapter 4 considers repurposing two anti-psychotic drugs i.e. quetiapine and olanzapine as suitable candidate anti-Cryptococcus drugs. The in vitro susceptibility results revealed that quetiapine and olanzapine have anti-cryptococcus activity and kill cells by compromising their membrane integrity. Importantly, the concentrations of drug tested were within the recommended dosage in the blood. Additionally, they acted in synergy with conventional drugs at concentrations that were lower than their defined MICs. It was also interesting to find that these two drugs chemosensitised macrophages, just like cytokines, which in turn, increase the appetite of macrophages against cryptococcal cells. The presented data from this thesis has highlighted the potential clinical application of aspirin, ibuprofen, CAS, quetiapine and olanzapine as candidate anti-cryptococcus drugs. More encouragingly, all the drugs were able to effect synergism at reduced concentrations, which in turn can minimize the issues of side effects. These compounds employed a killing mechanism that was efficient against cryptococcal cells, although of lower eukaryotic origin. Therefore, it is important to demonstrate the effectiveness of these drugs in higher eukaryotic host cells. Towards this end, animal studies should be used as model to establish their therapeutic benefits in higher eukaryotic hosts. The duality of these compounds should also be assessed, which may provide additional beneficial therapeutic outcomes such as to manage pathogen-emergent psychosis and out-of-control inflammatory responses. Lastly, it is also important to determine if the antimicrobial activities of these compounds also occurs in other medically important pathogens. | en_ZA |
| dc.description.abstract | Afrikaans: Die verskeinsel van verspreide Cryptococcus infeksie in MIV-besmette individue is 'n lewensgevaarlike infeksie, met ‘n sterftesyfer van 70% in sub-Sahara Afrika. Mense sterf as gevolg van komplikasies rondom die bestuur. So, daar is 'n behoefte aan alternatiewe medisyne vir beter bestuur van MIV-verwante krypto infeksie. Hierdie proefskrif het suksesvol in vitro anti-Cryptococcus aktiwiteit van: 1) anti-inflammatoriese middels (aspirien en ibuprofen), 2) aspirinaat-metaalkomplekse (KAS), en 3) anti-psigotiese middels (quetiapien en olanzapien) gedemonstreer. In hierdie proefskrif is EUCAST- riglyne gebruik wat ʼn gevoel van doeltreffendheid daarstel, wat baie belangrik is vir die verbetering van die pasiëntuitkomste. Hoofstuk 2 fokus op heraanwending van aspirien en ibuprofen as alternatiewe anti-Cryptococcus middels. Die belangrikste bevindings van hierdie deel van die proefskrif toon dat, al die getoetse gisstamme 'n dosis afhanklik reaksieprofiel teenoor aspirien en ibuprofen vertoon het. In vergelyking met aspirien, het ibuprofen ‘n groter antimikrobiese aksie uitgeoefen. Nog belangriker, die minimum inhiberende konsentrasie (MIK) van beide middels het die funksionering van makrofage nie negatief beïnvloed nie - eerder versterk hulle die fagositiese vermoë van makrofage om meer Cryptococcus selle te internaliseer. Dit is ook aangetoon dat ibuprofen in sinergie met flukonasool en amfoterisien B optree, teen laer konsentrasies as getoetste individuele konsentrasies. Ons bevindinge het getoon dat die antimikorobiese werking van aspirien en ibuprofen is via oksidatiewe skade. Hoofstuk 3 fokus op 'n afgeleide van aspirien nl. koper asielsalisilaat (KAS). KAS besit anti-fungale aktiwiteit teen Cryptococcus selle en tree op in sinergie met flukonasool en amfoterisien B teen laer konsentrasies as hul individuele getoetste konsentrasies. KAS dood ook selle via membraanskade a.g.v. reaktiewe suurstof spesies (RSS). Die effek van KAS het nie 'n negatiewe invloed op makrofage nie, maar verhoog eerder hul fagositiese funksie. In vergeleke met aspirien, het KAS gelei tot meer groei vermindering en minder toksisiteit. Huidiglik is een van die belangrikste uitdagings in die bestuur van verspreide Cryptococcus infeksies, die sekondêre komplikasies soos psigose. Daarom oorweeg hoofstuk 4 die heraanwending van twee anti-psigotiese middels, en wel quetiapien en olanzapien, as geskikte kandidaat anti-Cryptococcus middels. Die in vitro vatbaarheidsresultate het aangetoon dat quetiapien en olanzapien anti-Cryptococcus aktiwiteit het en selle dood deur hul membraanintegriteit te beskadig. Wat belangrik is, is dat die konsentrasies van middels wat getoets is, binne die aanbevole dosis in die bloed is Daarbenewens tree hulle in sinergie op met konvensionele medisyne, teen konsentrasies wat laer as hul gedefinieer MIK was. Dit was ook interessant om te sien dat hierdie twee middels makrofage chemosensiteer, net soos sitokiene, en so die aptyt van makrofage vir Cryptococcus-selle verhoog. Die data wat aangebied word in hierdie proefskrif het die potensiële kliniese toepassing van aspirien, ibuprofen, KAS, quetiapien en olanzapien as kandidaat anti-cryptococcus middels uitgelig. Al die middels was in staat om sinergisme te bewerkstellig teen verlaagde konsentrasie, wat op sy beurt die kwessies van newe-effekte kan verminder. Hierdie verbindings meganismes gebruik wat doeltreffende was om Cryptococcus-selle, van 'n laer eukariotiese oorsprong, te dood. Daarom is dit belangrik om die doeltreffendheid van die middels in hoër eukariotiese gasheerselle demonstreer. Dit ten doel moet dierestudies gebruik word as model om hul terapeutiese voordele in hoër eukariotiese gashere te vestig. Die dualiteit van hierdie verbindings moet ook beoordeel word, wat bykomende voordelige terapeutiese uitkomste kan lewer soos om patogeen-ontluikende psigose en onbeheerde inflammatoriese response te bestuur. Laastens is dit ook belangrik om te bepaal of hierdie verbindings se antimikrobiese aktiwiteit uitgebrei kan word na ander medies belangrike patogene. | af |
| dc.description.sponsorship | National Research Foundation (NRF) | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11660/6513 | |
| dc.language.iso | en | en_ZA |
| dc.publisher | University of the Free State | en_ZA |
| dc.rights.holder | University of the Free State | en_ZA |
| dc.subject | Cryptococcal infection | en_ZA |
| dc.subject | Aspirin | en_ZA |
| dc.subject | Ibuprofen | en_ZA |
| dc.subject | Copper acyl salicylate | en_ZA |
| dc.subject | Reactive oxygen species | en_ZA |
| dc.subject | Quetiapine | en_ZA |
| dc.subject | Olanzapine | en_ZA |
| dc.subject | Fluconazole | en_ZA |
| dc.subject | Macrophages | en_ZA |
| dc.subject | Psychosis | en_ZA |
| dc.subject | In vitro susceptibility | en_ZA |
| dc.subject | Phagocytose | en_ZA |
| dc.subject | AIDS (Disease) | en_ZA |
| dc.subject | Opportunistic infections | en_ZA |
| dc.subject | HIV infections -- Treatment | en_ZA |
| dc.subject | Thesis (Ph.D. (Microbial, Biochemical and Food Biotechnology))--University of the Free State, 2017 | en_ZA |
| dc.title | The repurposing of chemical compounds as anti-Cryptococcus drugs | en_ZA |
| dc.type | Thesis | en_ZA |