Cryptococcal meningitis manifests in approximately 10%
of individuals with untreated AIDS. The infection is typically caused by Cryptococcus neoformans
, a fungus that enters the body through the lungs and spreads to the spinal cord and causes inflammation. If left untreated, the infection can lead to coma and subsequent death.
is the leading cause of mortality in people living with HIV/AIDS, especially in sub-Saharan Africa. Typical treatment for the infection includes courses of amphotericin B and fluconazole; however, these treatments can often be associated with clinical failure. With these unfavorable outcomes, investigators have been on the hunt for alternative treatments.
In a presentation at the ASM/ESCMID Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance, a team of investigators presented their research, which explored the action of chloroquine (CQ) and primaquine (PQ) diphosphate on the growth of Cryptococcus
The investigators from South Africa determined the sensitivity of cryptococcal strains toward CQ and PQ and investigated the mode of action of both options in killing Cryptococcus
. The team also assessed the ability of CQ and PQ to sensitize macrophages.
Following a maximum exposure window of 48 hours, the direct effect of CQ and PQ showed a distinctive growth reduction on 8 cryptococcal isolates. The growth reduction ranged from 50 to 90% (p < 0.01) and 38-74% (p < 0.01), respectively, with CQ exerting a greater inhibitory effect. Minimum inhibitory concentrations (MICs) were 50 µM for CQ and 60 µM for PQ. The investigators indicate that at these MICs, the drugs possibly inhibited cryptococcal growth by adversely affecting the mitochondria.
Compared with non-treated cells, the loss of mitochondrial membrane potential (MMP) with CQ and PQ accounted for 43-60% (p < 0.01) and 52-65% (p < 0.01), respectively. “To the point, the loss of MMP resulted from a significant dislodging of cytochrome c (p < 0.05) from the mitochondria and overproduction of reactive oxygen species (p < 0.01), leaving the non-fermentative isolates with no other means of energy production,” the authors wrote.
The team also observed that CQ and PQ induced disruption of the cell wall integrity of the fungi, which occurred through the creation of pores (p < 0.05), leakage of cellular components (p < 0.05), and ultimately cell death after 24 hours.
Neither of the drugs had a negative effect on the macrophages, as a broad therapeutic index of 20:1 was recorded.
“Remarkably, CQ and PQ significantly enhanced the phagocytic efficiency of macrophages against Cryptococcus
by a maximum of 27% (p < 0.05) and 32% (p < 0.05), respectively at half their MICs,” the authors explained.
Based on the findings of this study, the investigators conclude that CQ and PQ may be strong candidates for controlling the growth of Cryptococcus
The study, “Chloroquine and Primaquine Diphosphate as Possible Alternative Drugs for the Treatment of Cryptococcal Infection
,” was presented in a poster session on Thursday, September 5, 2019, at ASM/ESCMID 2019 in Boston, Massachusetts.
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