scholarly journals Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Megan Okada ◽  
Ping Guo ◽  
Shai-anne Nalder ◽  
Paul A Sigala
Keyword(s):  
Antimalarial Drug ◽  
Antimalarial Activity ◽  
Protein Translation ◽  
Clinical Use ◽  
Serum Concentrations ◽  
Parasite Resistance ◽  
Specific Mechanism ◽  
Isopentenyl Pyrophosphate ◽  
Delayed Death ◽  
Dependent Mechanism

Doxycycline (DOX) is a key antimalarial drug thought to kill Plasmodium parasites by blocking protein translation in the essential apicoplast organelle. Clinical use is primarily limited to prophylaxis due to delayed second-cycle parasite death at 1–3 µM serum concentrations. DOX concentrations > 5 µM kill parasites with first-cycle activity but are thought to involve off-target mechanisms outside the apicoplast. We report that 10 µM DOX blocks apicoplast biogenesis in the first cycle and is rescued by isopentenyl pyrophosphate, an essential apicoplast product, confirming an apicoplast-specific mechanism. Exogenous iron rescues parasites and apicoplast biogenesis from first- but not second-cycle effects of 10 µM DOX, revealing that first-cycle activity involves a metal-dependent mechanism distinct from the delayed-death mechanism. These results critically expand the paradigm for understanding the fundamental antiparasitic mechanisms of DOX and suggest repurposing DOX as a faster acting antimalarial at higher dosing whose multiple mechanisms would be expected to limit parasite resistance.

scholarly journals Doxycycline has Distinct Apicoplast-Specific Mechanisms of Antimalarial Activity

2020 ◽  
Author(s):  
Megan Okada ◽  
Ping Guo ◽  
Shai-anne Nalder ◽  
Paul A. Sigala
Keyword(s):  
Antimalarial Drug ◽  
Antimalarial Activity ◽  
Protein Translation ◽  
Clinical Use ◽  
Serum Concentrations ◽  
Parasite Resistance ◽  
Specific Mechanism ◽  
Isopentenyl Pyrophosphate ◽  
Delayed Death ◽  
Dependent Mechanism

AbstractDoxycycline (DOX) is a key antimalarial drug thought to kill Plasmodium parasites by blocking protein translation in the essential apicoplast organelle. Clinical use is primarily limited to prophylaxis due to delayed second-cycle parasite death at 1-3 μM serum concentrations. DOX concentrations >5 μM kill parasites with first-cycle activity but have been ascribed to off-target mechanisms outside the apicoplast. We report that 10 μM DOX blocks apicoplast biogenesis in the first cycle and is rescued by isopentenyl pyrophosphate, an essential apicoplast product, confirming an apicoplast-specific mechanism. Exogenous iron rescues parasites and apicoplast biogenesis from first-but not second-cycle effects of 10 μM DOX, revealing that first-cycle activity involves a metal-dependent mechanism distinct from the delayed-death mechanism. These results critically expand the paradigm for understanding the fundamental antiparasitic mechanisms of DOX and suggest repurposing DOX as a faster-acting antimalarial at higher dosing whose multiple mechanisms would be expected to limit parasite resistance.

scholarly journals Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast

2007 ◽  
Vol 51 (10) ◽  
pp. 3485-3490 ◽  
Author(s):  
Erica L. Dahl ◽  
Philip J. Rosenthal
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Division ◽  
Antimalarial Activity ◽  
Mechanisms Of Action ◽  
Malaria Parasites ◽  
Delayed Effects ◽  
Delayed Death ◽  
Antimalarial Action ◽  
Multiple Antibiotics

ABSTRACT Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics.

Antimalarial activity of the bisquinoline trans-N1,N2-bis (7-chloroquinolin-4-yl)cyclohexane-1,2-diamine: comparison of two stereoisomers and detailed evaluation of the S,S enantiomer, Ro 47-7737.

1997 ◽  
Vol 41 (3) ◽  
pp. 677-686 ◽  
Author(s):  
R G Ridley ◽  
H Matile ◽  
C Jaquet ◽  
A Dorn ◽  
W Hofheinz ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Ex Vivo ◽  
The Other ◽  
Parasite Resistance ◽  
Curative Effect ◽  
Specific Process ◽  
Terminal Half Life ◽  
Detailed Evaluation ◽  
Oral Doses

The S,S enantiomer of the bisquinoline trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine, Ro 47-7737, is significantly more potent against chloroquine-resistant Plasmodium falciparum than the R,R enantiomer and the previously described racemate. Both the enantiomers and the racemate are more potent inhibitors of heme polymerization than chloroquine, and their activities are probably mediated by inhibition of this parasite-specific process. The S,S enantiomer, Ro 47-7737, was studied in more detail and proved to be a potent antimalarial in the treatment of P. vivax ex vivo and P. berghei in vivo. Its suppression of P. berghei growth in a mouse model (50% effective dose, 2.3 mg/kg of body weight) was equal to that of chloroquine and mefloquine, and Ro 47-7737 was found to be more potent than these two drugs in the Rane test, in which the curative effect of a single dose is monitored. The dose at which 50% of animals were permanently cured (34 mg/kg) was markedly superior to those of chloroquine (285 mg/kg) and mefloquine (> 250 mg/kg). When administered orally at 50 mg/kg, Ro 47-7737 also showed a faster clearance of parasites than either chloroquine or mefloquine, and unlike the other two compounds, Ro 47-7737 showed no recrudescence. In a study to compare prophylactic efficacies of oral doses of 50 mg/kg, Ro 47-7737 provided protection for 14 days compared to 3 days for mefloquine and 1 day for chloroquine. The good curative and prophylactic properties of the compound can be explained in part by its long terminal half-life. The ability to generate parasite resistance to Ro 47-7737 was also assessed. With a rodent model, resistance could be generated over eight passages. This rate of resistance generation is comparable to that of mefloquine, which has proved to be an effective antimalarial for many years. Toxicity liabilities, however, ruled out this compound as a candidate for drug development.

scholarly journals Exploratory Analysis into the in vitro and in silico Activity of E. fusca Lour. (Fabaceae) Elucidates Substantial Antiplasmodial Activity of the Plant

2021 ◽  
Author(s):  
Saiful Arefeen Sazed ◽  
Ohedul Islam ◽  
Sarah L. Bliese ◽  
Muhammad Riadul Haque Hossainey ◽  
Jakaria Shawon ◽  
...  
Keyword(s):  
Antimalarial Drug ◽  
Simulation Analysis ◽  
Antimalarial Activity ◽  
Dynamics Simulation ◽  
Drug Candidate ◽  
Phytochemical Investigation ◽  
High Degree ◽  
Emergence Of Resistance ◽  
First Time

The exploration of alternative antimalarial therapeutics is a requisite for the emergence of resistance against Artemisinin. Considering the required cost and time length of classical small molecule drug discovery process, phytochemical screening of traditionally used medicinal plant which are repertoire of active compounds with antimalarial activity has become popular. To investigate the antimalarial property of traditionally used medicinal plants, a number of Erythrina spp have been reviewed systematically where less studied E. fusca has been selected for further analysis. Phytochemical investigation yielded five compounds namely; Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol. In-vitro antimalarial drug sensitivity HRP-II ELISA was carried out against chloroquine (CQ) sensitive 3D7 and CQ-resistant Dd2 strains. Extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94 – 22 µg/mL) and these compounds have been reported here for the first time. Molecular docking analysis showed high binding energy (−9.0 ± 0.32 kcal/mole) indicating high degree of interaction between Phaseolin and 14 clinically important Plasmodium falciparum proteins at the active site. Stable interaction was also observed between ligand and protein from molecular dynamics simulation analysis with high free energy (−75.156 ± 11.459) that substantiates the potential of Phaseolin as an antimalarial drug candidate.

scholarly journals Mitochondrial type II NADH dehydrogenase of Plasmodium falciparum is dispensable and not the functional target of putative NDH2 quinolone inhibitors

2018 ◽  
Author(s):  
Hangjun Ke ◽  
Suresh M. Ganesan ◽  
Swati Dass ◽  
Joanne M. Morrisey ◽  
Sovitj Pou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Nadh Dehydrogenase ◽  
Antimalarial Activity ◽  
Reductase Activity ◽  
Proton Pumping ◽  
Type Ii ◽  
Long Time ◽  
Specific Inhibitors

AbstractThe battle against malaria has been substantially impeded by the recurrence of drug resistance in Plasmodium falciparum, the deadliest human malaria parasite. To counter the problem, novel antimalarial drugs are urgently needed, especially those that target unique pathways of the parasite, since they are less likely to have side effects. The mitochondrial type II NADH dehydrogenase of P. falciparum, PfNDH2 (PF3D7_0915000), has been considered a good prospective antimalarial drug target for over a decade, since malaria parasites lack the conventional multi-subunit NADH dehydrogenase, or Complex I, present in the mammalian mitochondrial electron transport chain (mtETC). Instead, Plasmodium parasites contain a single subunit NDH2, which lacks proton pumping activity and is absent in humans. A significant amount of effort has been expended to develop PfNDH2 specific inhibitors, yet the essentiality of PfNDH2 has not been convincingly verified. Herein, we knocked out PfNDH2 in P. falciparum via a CRISPR/Cas9 mediated approach. Deletion of PfNDH2 does not alter the parasite’s susceptibility to multiple mtETC inhibitors, including atovaquone and ELQ-300. We also show that the antimalarial activity of the fungal NDH2 inhibitor HDQ and its new derivative CK-2-68 is due to inhibition of the parasite cytochrome bc1 complex rather than PfNDH2. These compounds directly inhibit the ubiquinol-cytochrome c reductase activity of the malarial bc1 complex. Our results call into question the validity of PfNDH2 as an antimalarial drug target.ImportanceFor a long time, PfNDH2 has been considered an attractive antimalarial drug target. However, the conclusion that PfNDH2 is essential was based on preliminary and incomplete data. Here we generate a PfNDH2 KO (knockout) parasite in the blood stages of Plasmodium falciparum, showing that the gene is not essential. We also show that previously reported PfNDH2-specific inhibitors kill the parasites primarily via targeting the cytochrome bc1 complex, not PfNDH2. Overall, we provide genetic and biochemical data that help to resolve a long-debated issue in the field regarding the potential of PfNDH2 as an antimalarial drug target.

scholarly journals Investigation of antimalarial activity and cytotoxicity profiling of a Bangladeshi plant Syzygium cymosum

2020 ◽  
Vol 14 (08) ◽  
pp. 924-928
Author(s):  
Muhammad Riadul Haque Hossainey ◽  
Saiful Arefeen Sazed ◽  
Maisha Khair Nima ◽  
Mohammad Saydur Rahman ◽  
Tanvir Ashraf ◽  
...  
Keyword(s):  
Vero Cell ◽  
Cell Line ◽  
Crude Extract ◽  
Antimalarial Drug ◽  
Methanolic Extract ◽  
Antimalarial Activity ◽  
Chloroform Fraction ◽  
Moderate Activity ◽  
Plant Materials ◽  
Vero Cell Line

Introduction: The persistent increase of resistance to existing antimalarials underscores the needs for new drugs. Historically, most of the successful antimalarial are derived from plants. The leaves of the S. cymosum is one of the plant materials used by traditional healers in malaria-endemic areas in Bangladesh for treatment of malaria. Here, we investigated the crude extract and its fractions against chloroquine (CQ)-sensitive 3D7, CQ-resistant Dd2, and artemisinin (ART)-resistant IPC 4912 Mondulkiri strains of Plasmodium falciparum. Methodology: The antimalarial activities were tested using HRP II based in-vitro antimalarial drug sensitivity ELISA described by WWARN and half inhibitory concentrations (IC50) were calculated by non-linear regression analysis using GraphaPad Prism. The cytotoxicity of the crude methanolic extract was assessed using the MTT assay on Vero cell line. Results: The methanolic crude extract revealed promising activity against 3D7 (IC50 6.28 µg/mL), Dd2 (IC50 13.42 µg/mL), and moderate activity against IPC 4912 Mondulkiri (IC50 17.47 µg/mL). Among the fractionated portions, the chloroform fraction revealed highest activity against IPC 4912 Mondulkiri (IC50 1.65 µg/mL) followed by Dd2 (1.73 µg/mL) and 3D7 (2.39 µg/mL). The crude methanolic extract also demonstrated good selectivity with the selectivity indices of > 15.92, > 7.45, and > 6.91 against 3D7, Dd2, and IPC 4912, respectively when tested against Vero cell line. Conclusions: This is the first report on S. cymosum for its putative antimalarial activity, and is imperative to go for further phytochemical analyses in order to investigate possible novel antimalarial drug compound(s).

scholarly journals Antimalarial Activity of Brusatol Against Plasmodium Berghei Infected Mice and the Mechanism Revealed by Whole Transcriptome Sequencing (RNA-Seq) Analysis

2021 ◽  
Author(s):  
Yixin Ren ◽  
Shanshan Xu ◽  
Yuan Gao ◽  
Yufeng Chen ◽  
Xiaodong Dai ◽  
...  
Keyword(s):  
Effective Dose ◽  
Plasmodium Berghei ◽  
Antimalarial Activity ◽  
Control Group ◽  
Serum Concentrations ◽  
Rna Seq ◽  
Standard Drug ◽  
Brucea Javanica ◽  
Tnf Α ◽  
Ifn Γ

Abstract BackgroundRecently, artemsinin-resistant malaria strains and clinical cases have appeared in Southeast Asia. Reportedly, there are malaria mutants in Africa that are resistant to artemisinin and its derivatives. Thus, it’s imminent to develop new antimalarial drugs. Brucea javanica is an effective antimalarial drug recorded in Chinese traditional medicine, which has been widely used in the folk for hundreds of years. Brusatol is the main active constituent of Brucea Javanica, thus we studied the effects of brusatol on prevention of malaria infection in vivo. MethodsTo determine the antiplasmodial activity of brusatol, a four-day suppressive test was used by dividing 56 mice into 7 groups of 8 mice each and given 4mg/kg, 3mg/kg, 2mg/kg, 1mg/kg, 0.5mg/kg of brusatol, the standard drug ((artesunate of 140 mg/kg) and the vehicle (normal saline). The best effective dose was used in the following test. The effects of brusatol to plasmodium berghei transcription were tested through RNA-seq and the results were confirmed by RT-qPCR. We also explored the expression of TNF -α, IFN-γ, IL-4, IL-12 to evaluate antimalarial mechanism of brusatol to host by ELISA.ResultsThe results showed that brusatol effectively inhibited plasmodium berghei infection, the best effective dose was 2mg/kg, and the side effects of brusatol to liver and kidney were slight and reversible. The expressions of GSK3β, ATP6A, ATP6B, ATP6M, MSP-2, EMP1, CTCS in plasmodium were significantly lower after brusatol treatment compared with control, while the expression of AMA-1 was significantly increased. The serum concentrations of IFN-γ, TNF-α and IL-4 in artesunate and brusatol group decreased significantly compared with the control group, while there was no statistical difference of the serum concentrations of IL-12.ConclusionsTaken together, these results demonstrated brusatol could be a priority candidate for antimalarial medicine development.

scholarly journals ANDROGRAPHOLIDE AND ITS DERIVATIVE - A STORY OF ANTIMALARIAL DRUG DESIGN AND SYNTHESIS

2017 ◽  
Vol 9 ◽  
pp. 98
Author(s):  
Andrianopsyah Mas Jaya Putra ◽  
Chaidir . . ◽  
Muhammad Hanafi ◽  
Yuanjiang Pan ◽  
Arry Yanuar
Keyword(s):  
Crystal Structure ◽  
Molecular Docking ◽  
Antimalarial Drug ◽  
Antimalarial Activity ◽  
Comparative Modeling ◽  
Design And Synthesis ◽  
Geranylgeranyl Pyrophosphate Synthase ◽  
Nmr Data ◽  
1H Nuclear Magnetic Resonance ◽  
Green Procedure

Objective: Andrographolide was found to show moderate antimalarial activity against chloroquine-resistant strain of Plasmodium falciparum (PF). Itthus becomes an interesting lead for new antimalarial drugs. This study describes a molecular docking of andrographolide and its derivative into thebest PF geranylgeranyl pyrophosphate synthase (PFGGPPS) model.Methods: A comparative modeling of PFGGPPS based on a crystal structure of Plasmodium vivax GGPPS was optimized and conducted. This modelwas considered suitable for molecular docking. Partition coefficient of andrographolide was determined to assist its derivative design based onhydrophobicity property. Synthesis of the antimalarial drug was scaled up to 5 mm and identified by13 C- and 1H-nuclear magnetic resonance (NMR)spectroscopy.Results: The optimal comparative modeling of PFGGPPS was conducted on chain B (3PH7 chain B). The calculated coefficient partition ofandrographolide’s derivative was higher (+1.89), compared to that of andrographolide of +1.62. The NMR data of second and third synthesisexperiments were consistent at the 5-mmol scale.Conclusions: On the molecular docking of andrographolide into the model, an antimalarial andrographolide derivative design that is morehydrophobic than andrographolide was proposed since the stronger hydrophobicity property of drug, the better of its activity of the drug. Synthesisof this derivative with a simple and green procedure was found to be reproducible.

scholarly journals Why calpain inhibitors are interesting leading compounds to search for new therapeutic options to treat leishmaniasis?

Parasitology ◽  
2016 ◽  
Vol 144 (2) ◽  
pp. 117-123 ◽  
Author(s):  
VITOR ENNES-VIDAL ◽  
RUBEM FIGUEIREDO SADOCK MENNA-BARRETO ◽  
MARTA HELENA BRANQUINHA ◽  
ANDRÉ LUIS SOUZA DOS SANTOS ◽  
CLAUDIA MASINI D'AVILA-LEVY
Keyword(s):  
Therapeutic Options ◽  
New Drugs ◽  
Regulatory Agencies ◽  
Neglected Diseases ◽  
Clinical Use ◽  
Parasite Resistance ◽  
Chemotherapeutic Treatment ◽  
Leading Compounds ◽  
Opinion Article ◽  
Calpain Inhibitors

SUMMARYLeishmaniasis is a neglected disease, which needs improvements in drug development, mainly due to the toxicity, parasite resistance and low compliance of patients to treatment. Therefore, the development of new chemotherapeutic compounds is an urgent need. This opinion article will briefly highlight the feasible use of calpain inhibitors as leading compounds to search for new therapeutic options to treat leishmaniasis. The milestone of this approach is to take advantage on the myriad of inhibitors developed against calpains, some of which are in advanced clinical trials. The deregulated activity of these enzymes is associated with several pathologies, such as strokes, diabetes and Parkinson's disease, to name a few. In Leishmania, calpain upregulation has been associated to drug resistance and virulence. Whereas the difficulties in developing new drugs for neglected diseases are more economical than biotechnological, repurposing approach with compounds already approved for clinical use by the regulatory agencies can be an interesting shortcut to a successful chemotherapeutic treatment for leishmaniasis.

scholarly journals Retargeting azithromycin analogues to have dual-modality antimalarial activity

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Amy L. Burns ◽  
Brad E. Sleebs ◽  
Ghizal Siddiqui ◽  
Amanda E. De Paoli ◽  
Dovile Anderson ◽  
...  
Keyword(s):  
Plasmodium Knowlesi ◽  
Antimalarial Activity ◽  
Treatment Strategies ◽  
Food Vacuole ◽  
Parasite Development ◽  
Malaria Parasites ◽  
Killing Activity ◽  
Delayed Death ◽  
Artemisinin Combination Therapies

Abstract Background Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing ‘delayed-death’ activity against the parasite’s apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action. Results Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on ‘quick-killing’ activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity. Conclusion We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.

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