Repurposing of Aspirin and Ibuprofen as Candidate Anti-Cryptococcus Drugs

Abstract

The usage of fluconazole and amphotericin B in clinical settings is often limited by, among other things, drug resistance development and undesired side effects. Thus, there is a constant need to find new drugs to better manage fungal infections. Toward this end, the study described in this paper considered the repurposing of aspirin (acetylsalicylic acid) and ibuprofen as alternative drugs to control the growth of cryptococcal cells. In vitro susceptibility tests, including a checkerboard assay, were performed to assess the response of Cryptococcus neoformans and Cryptococcus gattii to the above-mentioned anti-inflammatory drugs. Next, the capacity of these two drugs to induce stress as well as their mode of action in the killing of cryptococcal cells was determined. The studied fungal strains revealed a response to both aspirin and ibuprofen that was dose dependent, with ibuprofen exerting greater antimicrobial action. More importantly, the MICs of these drugs did not negatively (i) affect growth or (ii) impair the functioning of macrophages; rather, they enhanced the ability of these immune cells to phagocytose cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B. The treatment of cryptococcal cells with aspirin or ibuprofen led to stress induction via activation of the high-osmolarity glycerol (HOG) pathway, and cell death was eventually achieved through reactive oxygen species (ROS)-mediated membrane damage. The presented data highlight the potential clinical application of aspirin and ibuprofen as candidate anti-Cryptococcus drugs.T he advent of HIV/AIDS has led to the emergence of species such as Cryptococcus neoformans and Cryptococcus gattii as important disease-causing microbes (1-3). To demonstrate this point, these species are reported to cause over 1 million infections worldwide, with the highest burden of infections being localized in resource-poor settings (4). In their paper, Perfect et al. argued that the management of fungal diseases is strongly dependent on capital resources available to a specific region (5). Based on the latter, Sebolai and Ogundeji further argued that it is not surprising for countries in sub-Saharan Africa, given the complex geopolitical and socioeconomic challenges that prevail in this region, to be unable to provide the necessary life-saving drugs, which are often expensive (6). Toward this end, a solution may be to repurpose already FDA-approved drugs that are cheap, such as aspirin (acetylsalicylic acid) and ibuprofen.We have previously reported that aspirin affected Cryptococcus cells in a number of ways: it (i) decreased capsule shedding, (ii) inhibited the production and trafficking of capsule-associated 3-hydroxy fatty acids, and (iii) inhibited cellular growth (7). In the current study, we build further on our prior antimicrobial work by drawing a comparison between the effects of aspirin and ibuprofen. Importantly, we also attempt to elucidate the mode of action employed by the two drugs in the killing of cryptococcal...

Copper Acyl Salicylate Has Potential as an Anti-Cryptococcus Antifungal Agent

“…At that concentration, CAS effected Ն50% growth reduction, compared to the drug-free control. Interestingly, we previously reported that aspirin (at the same drug concentration [1 mM]) also effected Ն50% growth reduction (8). When the antimicrobial activity of CAS was directly compared with that of aspirin against all 10 strains, however, CAS was noted to be more effective in reducing growth (data not shown).…”

“…Issues involving current antifungal drugs (amphotericin B and its side effects and fluconazole being fungistatic) only worsen the matter. Therefore, we have proposed a number of alternative drugs that may be considered to manage cryptococcal infections (8,18). The current study looked specifically at the effects of a metal complex, CAS, and was informed by our initial work on aspirin.…”

“…Moreover, the aspirinate-copper complex was pharmacologically more active than aspirin in laboratory animals (10). Based on those findings, it became the aim of the current study to determine whether an aspirinate-metal complex, i.e., copper acyl salicylate (CAS), could also exert antimicrobial effects on cryptococcal cells and, importantly, whether it would yield better results than those reported by Ogundeji and coworkers for aspirin (8).…”

“…Our group has actively sought to identify and to demonstrate "new" applications of "old" drugs, typically those that are FDA approved and are currently purposed to treat noninfectious conditions such as inflammation, as anti-Cryptococcus drugs. In one of our recent studies, we successfully demonstrated that the prototypical anti-inflammatory drug aspirin can be repurposed as an anti-Cryptococcus antifungal agent (8). However, the usage of aspirin in clinical settings can often lead to gastrointestinal toxicity (9).…”

The Repurposing of Anti-Psychotic Drugs, Quetiapine and Olanzapine, as Anti-Cryptococcus Drugs

“…In addition, fluconazole and amphotericin B MICs were based on those reported by Ogundeji et al (2016). The Ogundeji et al study and the current study were done at the same time, in the same laboratory.…”