The repurposing of chemical compounds as anti-Cryptococcus drugs

[摘要] 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.

[发布机构] University of the Free State