Nornidulin, A New Inhibitor of Plasmodium falciparum Malate: Quinone Oxidoreductase (PfMQO) from Indonesian Aspergillus sp. BioMCC f.T.8501

Abstract

This study aimed to obtain a microbial active compound as a novel antimalarial drug from Indonesian isolates. Target-based assays were used to screen for antimalarial activity against the parasite mitochondrial, Plasmodium falciparum malate:quinone oxidoreductase (PfMQO) enzyme. In total, 1600 crude extracts, composed from 800 fungi and 800 actinomycetes extracts, were screened against PfMQO, yielding six active extracts as primary hits. After several stages of stability tests, one extract produced by Aspergillus sp. BioMCC f.T.8501 demonstrated stable PfMQO inhibitory activity. Several purification stages, including OCC, TLC, and HPLC, were performed to obtain bioactive compounds from this active extract. All purification steps were followed by an assay against PfMQO. We identified the active compound as nornidulin based on its LC-MS and UV spectrum data. Nornidulin inhibited PfMQO activity at IC50 of 51 µM and P. falciparum 3D7 proliferation in vitro at IC50 of 44.6 µM, however, it had no effect on the growth of several mammalian cells. In conclusion, we isolated nornidulin from Indonesian Aspergillus sp. BioMCC f.T.8501 as a novel inhibitor of PfMQO, which showed inhibitory activity against the proliferation of P. falciparum 3D7 in vitro.

Insights into the Mechanism of Catalytic Activity of Plasmodium Parasite Malate-Quinone Oxidoreductase

“…In general, there are a variety of potent inhibitors, all of which bind to the quinone reaction site in a variety of oxidoreductases that use quinones as substrates. − This implies that the quinone-binding site is a possible druggable site in MQO. Using several approaches including drug screening, compounds have been identified that might inhibit MQO. ,,, However, to the best of our knowledge, no inhibitor has been yet reported that interacts with the quinone-binding site. To explore novel inhibitors targeting MQO, it will be necessary to fully understand the mechanism of action of MQO, for example, by solving the structure of enzyme–substrate complexes.…”

“…Using several approaches including drug screening, compounds have been identified that might inhibit MQO. 12 , 14 , 49 , 50 However, to the best of our knowledge, no inhibitor has been yet reported that interacts with the quinone-binding site. To explore novel inhibitors targeting MQO, it will be necessary to fully understand the mechanism of action of MQO, for example, by solving the structure of enzyme–substrate complexes.…”

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“…Saponins, on the other hand, possess antimalarial properties by causing erythrocytes to lyse through the destruction of their cell membranes [35,36]. Alkaloids have demonstrated the ability to decrease parasitemia levels by inhibiting the synthesis of parasite DNA and RNA [37]. While steroids and their derivatives have also been found to have antimalarial effects in various studies, the specific mechanism remains unclear.…”

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“…Malaria eradication has resulted in a decrease in morbidity and mortality [1]. Still, malaria control efforts over the last decade have been ineffective [2]. Malaria control is made worse by the COVID-19 pandemic, which affects the decline and slowdown of care for this infectious disease.…”

“…Malaria control is made worse by the COVID-19 pandemic, which affects the decline and slowdown of care for this infectious disease. This condition increased morbidity rates of 240 million cases and a mortality rate of around 627 thousand [2,3]. During the last 20 years, artemisinin combination treatment, or ACT, has been the main medication for treating various malaria infections.…”