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The impact of selected antibiotics on combating malaria infections was discovered in the mid of last century. Only recently, studies on their modes of action in malaria parasites have been initiated, prompted by the discovery of a prokaryotic organelle, the apicoplast. This plastid-derived structure, which originates from a secondary endosymbiotic...
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Citations
... Well-known antibiotics like sulfadoxine have been explored for their use in malaria treatment, but often they cause a delayed death phenotype or a mild parasite growth inhibition, which makes them inappropriate for malaria therapy when used alone (Pradel & Schlitzer, 2010). For this reason, antibiotics have been incorporated into nanoparticles to enhance their antimalarial properties, such as the anticoccidial drug monensin, a polyether ionophore with antimalarial activity against some Plasmodium species, including P. falciparum (Adovelande & Schrevel, 1996;D'Alessandro et al., 2015;Gumila et al., 1997). ...
Malaria, caused by different species of protists of the genus Plasmodium , remains among the most common causes of death due to parasitic diseases worldwide, mainly for children aged under 5. One of the main obstacles to malaria eradication is the speed with which the pathogen evolves resistance to the drug schemes developed against it. For this reason, it remains urgent to find innovative therapeutic strategies offering sufficient specificity against the parasite to minimize resistance evolution and drug side effects. In this context, nanotechnology‐based approaches are now being explored for their use as antimalarial drug delivery platforms due to the wide range of advantages and tuneable properties that they offer. However, major challenges remain to be addressed to provide a cost‐efficient and targeted therapeutic strategy contributing to malaria eradication. The present work contains a systematic review of nanotechnology‐based antimalarial drug delivery systems generated during the last 10 years.
This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease
... Doxycycline, a broad-spectrum tetracyclineclass antibiotic, is frequently used to treat Plasmodium spp. by killing erythrocytic-stage parasites that target the apicoplast [22], in combination with quinine. Several attempts have been made to demonstrate its distinctive anti-babesial effects in experimental animals [23][24][25]. ...
Background:
Human babesiosis is a worldwide disease caused by intraerythrocytic protozoa of the genus Babesia. It is transmitted by bites from ixodid ticks, and mechanically transmitted by blood transfusion. It is primarily treated with quinine and/or atovaquone, which are not readily available in China. In this study, we developed a novel treatment regimen involving doxycycline monotherapy in a patient with severe Babesia venatorum infection as an alternative therapeutic medication. The aim of our study is to provide a guidance for clinical practice treatment of human babesiosis.
Case presentation:
A 73-year-old man who had undergone splenectomy and blood transfusion 8 years prior, presented with an unexplained fever, headache, and thrombocytopenia, and was admitted to the Fifth Medical Center of the PLA General Hospital. He was diagnosed with B. venatorum infection by morphological review of thin peripheral blood smears, which was confirmed by multi-gene polymerase chain reaction (PCR), and sequencing of the entire 18s rRNA and partial β-tubulin encoding genes, as well as isolation by animal inoculation. The doxycycline monotherapy regimen (peros, 0.1 g bisindie) was administered following pharmacological guidance and an effective outcome was observed. The patient recovered rapidly following the doxycycline monotherapy. The protozoan load in peripheral blood samples decreased by 88% in hematocrit counts after 8 days, and negative PCR results were obtained after 90 days of follow-up at the hospital. The treatment lasted for 3 months without any side effects or sequelae. The nine-month follow-up survey of the patient did not reveal any signs of recrudescence or anti-babesial tolerance.
Conclusions:
We have reported a clinical case of successful doxycycline monotherapy for human babesiosis caused by B. venatorum, which provides an optional medical intervention for human babesiosis.
... treated with antibiotics targeting the apicoplast prokaryotic-like ribosome, like azithromycin 14 , clindamycin 15 and tetracyclines 16 lead to parasites that grow and divide but produce progeny of schizonts that inherited non-functional apicoplasts and are unable to differentiate into merozoites that are necessary to invade new erythrocytes, causing a "Delayed-Death" phenomenon. [17][18][19] Thus, drugs targeting the apicoplast can be used as monotherapy for prophylaxis or in combination with other rapid acting antimalarials for management of active malarial infection. ...
Malaria is caused by the parasite Plasmodium falciparum, which contains an essential non-photosynthetic plastid called the apicoplast. A single DNA polymerase, apPOL, is targeted to the apicoplast, where it replicates and repairs the genome. apPOL has no direct orthologs in mammals and is considered a promising drug target for the treatment and/or prevention of malaria. We previously reported screening the Malaria Box to identify MMV666123 as an inhibitor of apPOL. Herein we extend our studies and report structure-activity relationships for MMV666123 and identify key structural motifs necessary for inhibition. Although attempts to crystallize apPOL with the inhibitor were not fruitful, kinetic analysis and crystal structure determinations of WT and mutant apo-enzymes, facilitated model building and provided insights into the putative inhibitor binding site. Our results validate apPOL as an antimalarial target and provide an avenue for the design of high potency, specific inhibitors of apPOL and other A-family DNA polymerases.
... Just like mitochondria, apicoplast has its DNA (about 35 kb) with various processes following the mechanism of prokaryotic DNA. Therefore some antibacterial compounds can work slow antimalarial activity 52,53 . For example, antibiotics used for antimalarials are clindamycin, tetracycline, macrolides, and chloramphenicol. ...
... For example, antibiotics used for antimalarials are clindamycin, tetracycline, macrolides, and chloramphenicol. The use of antibiotics as antimalarials given in combination in clinical trials has good effects such as clindamycin and quinine [53][54][55] . ...
Apigenin is a natural compound that is present in a number of plants such as celery, parsley, grapes, chamomile, onions, maize, tea, sugar, and sprouts belonging to the flavone subclass of flavonoid. Like vitamins, anti-inflammatory medications, vasodilators, anticoagulation, antidiabetes, anticancer, antimalarial drugs, apigenin has many pharmacological functions. The main therapeutic agent for malarial disease is apigenin, based on in vitro, in vivo, and silico research. The purpose of the review is to describe the mechanism of apigenin as an antimalarial agent. Apigenin has antimalarial mechanisms that are confirmed to induce ABCC1 transporters, inhibit protein kinase (Pf RIO-2 kinase) (right open reading frame-2 protein kinase), and act as an antioxidant.
... This means that the antibiotics need two replicative cycles to exert their action against the parasites. This slow onset of action cannot only be seen in vitro, but also in vivo in monotherapy treatments of malaria, and should therefore not be considered as the main chemotherapy to treat acute P. falciparum malaria [24,25]. The reason for the delayed death phenotype has been partly elucidated recently. ...
Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the anti-malarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections.
... The design and synthesis of 2,4-diaminoquinazoline analogs as dual inhibitors active against falcipain-2 (FP-2) and PfDHFR were reported by Chen et al. [216] via fragments assembly method. During the study, authors discovered the best compound 18 (Fig. 14) through lead optimization which was reported with high potency against FP-2 (IC 50 [217]. ...
Malaria is an endemic disease, prevalent in tropical and subtropical regions which cost half of million deaths annually. The eradication of malaria is one of the global health priority nevertheless, current therapeutic efforts seem to be insufficient due to the emergence of drug resistance towards most of the available drugs, even first-line treatment ACT, unavailability of the vaccine, and lack of drugs with a new mechanism of action. Intensification of antimalarial research in recent years has resulted into the development of single dose multistage therapeutic agents which has advantage of overcoming the antimalarial drug resistance. The present review explored the current progress in the development of new promising antimalarials against prominent target proteins that have the potential to be a clinical candidate. Here, we also reviewed different aspects of drug resistance and highlighted new drug candidates that are currently in a clinical trial or clinical development, along with a few other molecules with excellent antimalarial activity overs ACTs. The summarised scientific value of previous approaches and structural features of antimalarials related to the activity are highlighted that will be helpful for the development of next-generation antimalarials.
... For a better perspective of the present study, it is important to note that the modern day malaria parasite is not a simple organism but a highly evolved parasite that represents a hybrid of prokaryotic bacteria and a eukaryotic primordial cell (Waller and McFadden, 2005). This endosymbiotic origin of malaria parasite is the reason why this parasite is killed by diverse antibiotics (Pradel and Schlitzer, 2010). Hence plants such as T catappa with ethnopharmacological reputation for restricting growth of parasites, controlling fever and producing antibiotics make them worthy for exploration against malaria. ...
Ethnopharmacological relevance
Terminalia catappa L. (West Indian-Almond) is a medicinal plant used in traditional medicine for the treatment of infectious diseases. Moreover, various organic extracts prepared from this plant have been reported to exhibit antiplasmodial activity.
Aim of the study
The need for new antimalarials is still an urgency driven by the alarmingly high burden of malaria in endemic regions, with multitude of people dying annually. We have previously identified an endophytic fungus Aspergillus niger 58 harboured by T. catappa as having promising specialized secondary metabolites against the malaria parasites. In the present study, we report the antiplasmodial activity-guided chromatographic isolation of some metabolites secreted by this endophytic fungus.
Materials and methods
The SYBR Green I-based fluorescence microtiter plate assay was used to monitor the growth of Plasmodium falciparum parasites in culture in the presence and absence of inhibitors and results were validated by microscopic analysis of Giemsa-stained culture smears. Giemsa-stain microscopy was also used to study the cell cycle stage-specific action of selected fractions.
Results
The results revealed that the multidimensional purification of the crude extract (IC50: 4.03 μg/mL) provided RPHPLC F17 (IC50: 0.09 μg/mL) and RPHPLC F18 (IC50: 0.1 μg/mL) with activity against P. falciparum 3D7 (Pf3D7) strain. Moreover, both fractions at IC99 (0.5 μg/mL) exhibited multi-stages action by targeting all the three stages of the life cycle of blood-stage Pf3D7. Two compounds, flavasperone (1) and aurasperone A (2) were isolated, of which aurasperone A exhibited good potency against Pf3D7 (IC50: 4.17 μM) and P. falciparum INDO (PfINDO) (IC50: 3.08 μM).
Conclusion
Our study adds credence to the notion that endophytic extracts are potential storehouses for potent specialized secondary metabolites that can be harnessed to fight the malaria parasite and reduce the burden of this disease worldwide. An endophyte that can be cultured in laboratory with ability to secrete promising metabolites of medicinal value holds the promise of conserving Nature from the threat of annihilation of flora for medicinal purposes.
Keywords: Aspergillus niger 58; Bioguided fractionation; Antiplasmodial; Stage specific action
... Enrofloxacin inhibits DNA gyrase, a prokaryotic type II topoisomerase, therefore, blocks prokaryotic DNA replication by hindering the untangling DNA during replication, and results in the linearization of the circular DNA, thus causing the death of prokaryotic organisms without affecting the mammalian topoisomerase [9][10][11]. DNA gyrase is made of two subunits, namely, DNA gyrase subunit A and DNA gyrase subunit B. Enrofloxacin has antibacterial, anti-anaplasma, antileishmanial, antitrypanosomal, anti-neospora, and anti-toxoplasma activities [12][13][14][15][16][17][18]. ...
Objectives: Enrofloxacin, a fluoroquinolone antibiotic, is an inhibitor of prokaryotic topoisomerase II with antibacterial and antiparasitic activities. The study aimed to evaluate the inhibitory effect of enrofloxacin on Babesia species and Theileria equi in vitro and in vivo. Methods: The inhibitory effects of enrofloxacin were evaluated in vitro cultures using in vitro inhibition assay of three Babesia species and Theileria equi; furthermore, the in vivo inhibitory effect of enrofloxacin was evaluated in the mice model of Babesia microti. Results: The IC50 values of enrofloxacin were 4.9, 4.5, 4, and 3.9 nM for B. bovis, B. bigemina, B. caballi, and B. equi, respectively. Enrofloxacin at a dose rate of 10 mg/kg resulted in a 92.9 % inhibition of Babesia microti growth in BALB/c mice. Combination therapy of enrofloxacin at a dose rate of 5 mg/kg with diminazene aceturate at a dose rate of 12.5 mg/kg resulted in 93.83 % inhibition of Babesia microti growth in BALB/c mice. Conclusions: Enrofloxacin might be used for drug therapy in babesiosis.
Keywords: Enrofloxacin, Babesia, Theileria equi, In vitro, In vivo.
Drug and Drug AbuseVolume 1(1): 2-6
doi:10.31487/j.DDA.2019.01.02
... While several drugs have been used to treat malaria, drug-resistant strains of Plasmodium are quickly spreading over the affected countries in Asia and Africa. Most recently, combined treatment with antibiotics such as azithromycin is frequently employed [75]. Antibiotics target organellar replication, transcription, and translation and affect the mitochondria and the apicoplast of the parasite. ...
... Unfortunately, some of these compounds might be toxic to humans at high doses Yellow, iron-sulfur cluster assembly machinery SUF, three-step synthesis, seven proteins required. Only key metabolites are shown, ALA-δ-aminolevulinic acid, DHAP-dihydroxyacetone-phosphate, DOXP-1-deoxy-d-xylulose 5-phosphate, PEP-phosphoenolpyruvate; in bold, production of cosubstrates ATP and NADH from PEP [71,75], and clinical trials are needed to determine the efficiency of these new therapeutics. In addition, further research is expected to develop more efficient ones. ...
A substantial portion of eukaryote diversity consists of algae with complex plastids, i.e., plastids originating from eukaryote-to-eukaryote endosymbioses. These plastids are characteristic by a deviating number of envelope membranes (higher than two), and sometimes a remnant nucleus of the endosymbiont alga, termed the nucleomorph, is present. Complex plastid-bearing algae are therefore much like living matryoshka dolls, eukaryotes within eukaryotes. In comparison, primary plastids of Archaeplastida (plants, green algae, red algae, and glaucophytes) arose upon a single endosymbiosis event with a cyanobacterium and are surrounded by two membranes. Complex plastids were acquired several times by unrelated groups nested within eukaryotic heterotrophs, suggesting complex plastids are somewhat easier to obtain than primary plastids. This is consistent with the existence of higher-order and serial endosymbioses, i.e., engulfment of complex plastid-bearing algae by (tertiary) eukaryotic hosts and functional plastid replacements, respectively. Plastid endosymbiosis is typical by a massive transfer of genetic material from the endosymbiont to the host nucleus and metabolic rearrangements related to the trophic switch to phototrophy; this is necessary to establish metabolic integration of the plastid and control over its division. Although photosynthesis is the main advantage of plastid acquisition, algae that lost photosynthesis often maintain complex plastids, suggesting their roles beyond photosynthesis. This chapter summarizes basic knowledge on acquisition and functions of complex plastid.
... [16] There are antibiotics used against plasmodia, particularly in combination with standard antimalarials to treat drug-resistant parasites. [17,18] Therefore, antimicrobial agents may be also active for malaria treatment and prophylaxis. [19,20] Since antibactericidal and antimalarial multidrug resistance is a challenge to public health, the identification of new effective drugs remains as an important tool to the infectious diseases control effort. ...
Background: Antibiotic resistance is a worldwide problem that poses a serious threat to human health, limiting the therapeutic options for bacterial infections. The spread of falciparum-resistant malaria is also concerning, making the patient treatment an extremely difficult task. Those facts have heightened the interest to find alternate options to treat infections caused by drug-resistant microorganisms. Objective: Considering the importance of the development of new substances with antibacterial and antimalarial properties, the present study aimed to investigate the activity of the aqueous extract of stem bark of Bowdichia virgilioides (AEBv). This plant is commonly used in Brazilian folk medicine to treat a wide range of illnesses, including signs and symptoms associated with malaria. Materials and Methods: The AEBv was assayed for toxicity against two cell lines and Artemia salina larvae. In vitro activity of the extract was screened against a panel of Gram-positive and Gram-negative bacteria, a chloroquine-resistant (W2) and a chloroquine-sensitive (3D7) Plasmodium falciparum strains. The extract was also tested as antimalarial in vivo against Plasmodium berghei. Results: The AEBv presented no significant toxicity and was found to exert in vitro growth inhibitory effect against the tested bacterial species. The lowest minimal inhibitory concentration was reported for Staphylococcus aureus (0.125 mg/ml) followed by Staphylococcus epidermidis and Staphylococcus saprophyticus (0.50 mg/ml). B. virgilioides extract showed weak in vitro antimalarial activity against P. falciparum. A preliminary phytochemical analysis revealed the presence of flavonoids, phenolic groups, terpenoids, saponins, and tannins and the absence of alkaloids. Conclusion: The AEBv showed promising activity against Gram-positive microorganisms. © 2018 Pharmacognosy Magazine | Published by Wolters Kluwer-Medknow.
