The pathogenesis of human malarial parasite Plasmodium falciparum is interlinked with the timely controlled gene expression during its complex life cycle. Therefore, epigenetic mechanisms are of paramount importance for parasite gene expression. PfGCN5 histone acetyltransferase (HAT), an essential enzyme, acetylates histone 3 and regulates global gene expression in the parasite. Here, we show the existence of a novel proteolytic processing of PfGCN5 that is crucial for its activity in vivo. We find that a cysteine protease like enzyme is required for the processing of PfGCN5 protein. Immunofluorescence and immuno-EM analysis suggest that the processing event occurs around the digestive vacuole of the parasite following the classical ER-Golgi secretory pathway before it reaches nucleus. Furthermore, blocking of PfGCN5 processing leads to the concomitant reduction of protein occupancy at the gene promoters with reduced H3K9 acetylation level, highlighting the important correlation between the processing event and its activity. Altogether, our study reveals a unique processing event of a nuclear protein PfGCN5 with unforeseen role of a food vacuolar cysteine protease with possibility of the development of new antimalarials against these targets.
Helicobacter pylori, a type 1 carcinogen accounts for numerous gastric cancer-related deaths worldwide. Repurposing existing drugs or developing new ones for a combinatorial approach against increasing anti-microbial resistance is the need of the hour. This study highlights the efficacy of acriflavine hydrochloride (ACF-HCl) in inhibiting the growth of H. pylori reference strain and antibiotic-resistant clinical isolates at low concentrations. ACF-HCl inhibits H. pylori growth at MIC value ten times less than in E. coli, another Gram-negative bacteria. Furthermore, ACF-HCl demonstrates synergistic effect with clarithromycin, a commonly used antibiotic against H. pylori. ACF-HCl treatment also eradicates H. pylori infection in the mice model efficiently. Our in vitro data indicate that bacterial membrane is the prime target. The novel action of ACF-HCl against antibiotic-resistant clinical isolates, synergistic effect with the conventional antibiotic clarithromycin and eradication of H. pylori from infected mice highlights the potential of ACF-HCl as a promising therapeutic agent against H. pylori by itself as well as for combinatorial therapy.
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More than sesquicentennial years of malarial research, however the unique malarial parasite, Plasmodium still bewilders us with its atypical characteristic features. Elimination strategies, deeper knowledge of the parasite biology and pathways can help combat this global health concern that affects ∼250 million people annually. In this review, we unveil an unusual phenomenon observed in the parasite proteome, N-terminal extensions in proteins and highlight that the proteases that may be involved in their processing events, are potential candidates to target this pathogen. Plasmodium encodes larger proteins as compared to its eukaryotic counterparts with homology regions present in the C-terminus of the protein. In contrast, the function of unusual extensions in the N-terminus remains mostly elusive. This novelty observed in Plasmodium proteins is collated here with a focus on replication proteins. The plausible functions and prevalence of these extensions, despite the reduction in genome size, through the parasite evolution are also mentioned. We hypothesize that these extensions, propagated via the energy consuming cellular processes in the otherwise host-dependent obligate parasite, are beneficial to the parasite in ways that are yet to be explored. Consequently, targeting the proteolytic processing of these proteins and the involved proteases would serve as a new drug development regimen to tackle the emerging resistance in parasites to existing antimalarials.
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