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.

scholarly journals Transfected Plasmodium knowlesi Produces Bioactive Host Gamma Interferon: a New Perspective for Modulating Immune Responses to Malaria Parasites

2003 ◽  
Vol 71 (8) ◽  
pp. 4375-4381 ◽  
Author(s):  
Hastings Ozwara ◽  
Jan A. M. Langermans ◽  
Clemens H. M. Kocken ◽  
Annemarie van der Wel ◽  
Peter H. van der Meide ◽  
...  
Keyword(s):  
Plasmodium Knowlesi ◽  
Gamma Interferon ◽  
Parasite Development ◽  
Malaria Parasites ◽  
Developmentally Regulated ◽  
Apical Membrane Antigen 1 ◽  
Ifn Γ ◽  
New Perspective ◽  
First Time

ABSTRACT Transgenic pathogenic microorganisms expressing host cytokines such as gamma interferon (IFN-γ) have been shown to manipulate host-pathogen interaction, leading to immunomodulation and enhanced protection. Expression of host cytokines in malaria parasites offers the opportunity to investigate the potential of an immunomodulatory approach by generating immunopotentiated parasites. Using the primate malaria parasite Plasmodium knowlesi, we explored the conditions for expressing host cytokines in malaria parasites. P. knowlesi parasites transfected with DNA constructs for expressing rhesus monkey (Macaca mulatta) IFN-γ under the control of the heterologous P. berghei apical membrane antigen 1 promoter, produced bioactive IFN-γ in a developmentally regulated manner. IFN-γ expression had no marked effect on in vitro parasite development. Bioactivity of the parasite-produced IFN-γ was shown through inhibition of virus cytopathic effect and confirmed by using M. mulatta peripheral blood cells in vitro. These data indicate for the first time that it is feasible to generate malaria parasites expressing bioactive host immunomodulatory cytokines. Furthermore, cytokine-expressing malaria parasites offer the opportunity to analyze cytokine-mediated modulation of malaria during the blood and liver stages of the infection.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

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.

scholarly journals Ex VivoMaturation Assay for Testing Antimalarial Sensitivity of Rodent Malaria Parasites

2016 ◽  
Vol 60 (11) ◽  
pp. 6859-6866 ◽  
Author(s):  
Zi Wei Chang ◽  
Benoit Malleret ◽  
Bruce Russell ◽  
Laurent Rénia ◽  
Carla Claser
Keyword(s):  
Ex Vivo ◽  
Single Step ◽  
Parasite Development ◽  
Ring Stage ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Parasite Biology

ABSTRACTEx vivoassay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-termin vitroculture andex vivoantimalarial susceptibility assays are relatively cumbersome, relying onin vivopassage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stagePlasmodium berghei,P. yoelii, andP. vinckei vinckeiusing a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.

scholarly journals Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine

2007 ◽  
Vol 52 (2) ◽  
pp. 705-715 ◽  
Author(s):  
Sanjay Kumar ◽  
Sajal Kumar Das ◽  
Sumanta Dey ◽  
Pallab Maity ◽  
Mithu Guha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Malaria Parasite ◽  
Spin Trap ◽  
Antimalarial Activity ◽  
Lipid Peroxide ◽  
Food Vacuole ◽  
Mitochondrial Potential ◽  
Free Heme

ABSTRACT A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (KD = 12 to 20 μM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H2O2, and hydroxyl radical (·OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (ΔΨm) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of ·OH may be mainly responsible for the antimalarial effect of AASMP since ·OH scavengers such as mannitol, as well as spin trap α-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial.

In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites

2001 ◽  
Vol 87 (3) ◽  
pp. 239-244 ◽  
Author(s):  
L. Delhaes ◽  
H. Abessolo ◽  
L. Berry ◽  
P. Delcourt ◽  
L. Maciejewski ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Malaria Parasites

Plasmodium knowlesi: In vitro evaluation of antimalarial activity of folic acid inhibitors

1971 ◽  
Vol 30 (1) ◽  
pp. 88-93 ◽  
Author(s):  
Gerald J. McCormick ◽  
Craig J. Canfield ◽  
Gloria P. Willet
Keyword(s):  
Folic Acid ◽  
Plasmodium Knowlesi ◽  
Antimalarial Activity ◽  
In Vitro Evaluation

scholarly journals In Vitro Activity of Riboflavin against the Human Malaria Parasite Plasmodium falciparum

2000 ◽  
Vol 44 (1) ◽  
pp. 88-96 ◽  
Author(s):  
Thomas Akompong ◽  
Nafisa Ghori ◽  
Kasturi Haldar
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Food Vacuole ◽  
Host Cells ◽  
Asexual Parasite ◽  
Human Malaria Parasite ◽  
Human Malaria ◽  
Average Size

ABSTRACT The human malaria parasite Plasmodium falciparumdigests hemoglobin and polymerizes the released free heme into hemozoin. This activity occurs in an acidic organelle called the food vacuole and is essential for survival of the parasite in erythrocytes. Since acidic conditions are known to enhance the auto-oxidation of hemoglobin, we investigated whether hemoglobin ingested by the parasite was oxidized and whether the oxidation process could be a target for chemotherapy against malaria. We released parasites from their host cells and separately analyzed hemoglobin ingested by the parasites from that remaining in the erythrocytes. Isolated parasites contained elevated amounts (38.5% ± 3.5%) of oxidized hemoglobin (methemoglobin) compared to levels (0.8% ± 0.2%) found in normal, uninfected erythrocytes. Further, treatment of infected cells with the reducing agent riboflavin for 24 h decreased the parasite methemoglobin level by 55%. It also inhibited hemozoin production by 50% and decreased the average size of the food vacuole by 47%. Administration of riboflavin for 48 h resulted in a 65% decrease in food vacuole size and inhibited asexual parasite growth in cultures. High doses of riboflavin are used clinically to treat congenital methemoglobinemia without any adverse side effects. This activity, in conjunction with its impressive antimalarial activity, makes riboflavin attractive as a safe and inexpensive drug for treating malaria caused by P. falciparum.

Sign in / Sign up

Export Citation Format

Share Document