Murad A. Mubaraki

Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria

There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc1. Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.

Metabolite footprinting of Plasmodium falciparum following exposure to Garcinia mangostana Linn. crude extract.

Multidrug resistant Plasmodium falciparum is the major health problem in the tropics. Discovery and development of new antimalarial drugs with novel modes of action is urgently required. The aim of the present study was to investigate antimalarial activities of Garcinia mangostana Linn. crude ethanolic extract including its bioactive compounds as well as the metabolic footprinting of P. falciparum following exposure to G. mangostana Linn. extract. The median (range) IC50 (concentration that inhibits parasite growth by 50%) values of ethanolic extract of G. mangostana Linn., α-mangostin, β-mangostin, gartanin, 9-hydroxycarbaxathone, artesunate, and mefloquine for 3D7 vs K1 P. falciparum clones were 12.6 (10.5-13.2) vs 4.5 (3.5-6.3) μg/ml, 7.3 (7.1-8.5) vs 5.0 (3.7-5.9) μg/ml, 47.3 (46.8-54.0) vs 35.0 (30.0-43.7) μg/ml, 9.2 (8.1-11.9) vs 6.8 (6.2-9.1) μg/ml, 0.6 (0.4-0.8) vs 0.5 (0.4-0.7) μg/ml, 0.4 (0.2-1.2) vs 0.7 (0.4-1.0)ng/ml, and 5.0 (4.2-5.0) vs 2.7 (2.5-4.6) ng/ml, respectively. The action of G. mangostana Linn. started at 12 h of exposure, suggesting that the stage of its action is trophozoite. The 12-h exposure time was used as a suitable exposure time for further analysis of P. falciparum footprinting. G. mangostana Linn. extract was found to target several metabolic pathways particularly glucose and TCA metabolisms. The malate was not detected in culture medium of the exposed parasite, which may indirectly imply that the action of G. mangostana Linn. is through interruption of TCA metabolism.

A prospective evaluation of synergistic effect of sulbactam and tazobactam combination with meropenem or colistin against multidrug resistant Acinetobacter baumannii

The present study evaluates the synergistic effect of sulbactam/tazobactam in combination with meropenem or colistin against multidrug resistant (MDR) Acinetobacter baumannii isolated from hospitalized patients from a tertiary care hospital in Saudi Arabia. During the study period, 54 multidrug and carbapenem-resistant isolates of A. baumannii isolates were collected from blood and respiratory samples of patients with ventilator-associated pneumonia or bacteremia. Microbroth checkerboard assay (CBA) and E-test were performed to look for synergistic interface of sulbactam and tazobactam with meropenem or colistin. All 54 MDR isolates of A. baumannii were resistant to carbapenem. Minimum inhibitory concentration [50/90] value against sulbactam, tazobactam, meropenem, colistin was found to be 64/128, 64/128, 64/256, and 0.5/1.0 respectively. Synergy was detected in more isolates with CBA compared to E-test. All four combinations showed significant synergistic bactericidal activity. However, the combination with colistin showed greater synergistic effect than combination with meropenem. Antagonism was not detected with any of the combinations and any method, but indifference was seen in tazobactam and colistin combination alone. A significant bactericidal effect was seen with sulbactam combination with meropenem or colistin in both methods. A combination therapy can be a choice of treatment. As colistin is known to exhibit nephrotoxicity, the combination of sulbactam and meropenem might be considered as an alternative antibiotic treatment for such multi- and extremely resistant bacteria. Yet, sample size is small in our study, so further well-designed in vitro and clinical studies on large scale should confirm our findings.

Indigofera oblongifolia leaf extract regulates spleen macrophage response during Plasmodium chabaudi infection

Malaria is a major health problem that still affects numerous countries. The current study aimed to identify the role of Indigofera oblongifolia leaf extract in regulating mouse spleen macrophages during the progression of Plasmodium chabaudi infection. Three doses of the leaf extract (100, 200, and 300 mg/kg) were administered to mice inoculated with P. chabaudi infected erythrocytes. The weight of the infected mice improved after the treatment with I. oblongifolia. The infection causes disorganization of macrophage distribution in the spleen. After the mice had been treated with the leaf extract, the macrophages appeared to be reorganized in the white and red pulp areas. In addition, the I. oblongifolia leaf extract (IOLE) significantly increased the total antioxidant capacity of the mice spleens infected with P. chabaudi. The phagocytic activity of spleen macrophages was increased in the infected group as indicated by the significant decrease in the number of fluorescent particles in the spleen sections. This number increased in the mice spleens after treatment with IOLE. Based on these results, it is suggested that IOLE regulate macrophage response of the spleen during the blood stage of malaria in mice.

Vitamin D receptor regulates intestinal inflammatory response in mice infected with blood stage malaria

Malaria is a harmful disease affecting both tropical and subtropical countries and causing sometimes fatal complications. The effects of malaria-related complications on the intestine have been relatively neglected, and the reasons for the intestinal damage caused by malaria infection are not yet clear. The present study aims to evaluate the influence of intestinal vitamin D receptor on host-pathogen interactions during malaria induced in mice by Plasmodium chabaudi. To induce the infection, animals were infected with 106P. chabaudi-parasitized erythrocytes. Mice were sacrificed on day 8 post-infection. The infected mice experienced a significant body weight loss and parasitaemia affecting about 46% of RBCs. Infection caused marked pathological changes in the intestinal tissue indicated by shortening of the intestine and villi. Moreover, the phagocytic activity of macrophages increased significantly (P < 0.01) in the infected villi compared to the non-infected ones. Infection by the parasite also induced marked upregulation of nuclear factor-kappa B, inducible nitric oxide synthase, Vitamin D Receptor, interleukin-1β, tumour necrosis factor alpha and interferon gamma-mRNA. It can be implied from this that vitamin D receptor has a role in regulating malarial infection.

Ameliorative role of Ziziphus spina-christi leaf extracts against hepatic injury induced by Plasmodium chabaudi infected erythrocytes

One of the most common deadliest parasitic diseases is Malaria. The biology and the pathogenesis of this fascinating parasite are not yet fully understood which make discovering effective alternative drugs a challenging task. Moreover, the emergence of resistant strains added an additional burden in the journey of malaria elimination. Traditional medicine used to be an alternative therapy choice owing to the presence of potent natural products. Ziziphus spina-christi (L.) considered being one of the common potent natural plant in gulf region and other nations. Therefore, this study designed to evaluate the ameliorative role of Z. spina-christi leaf extracts (ZSCLE) against Plasmodium chabaudi-induced hepatic injury. The study involved three groups were as follows; a vehicle control group, infected with 106P. chabaudi-parasitized erythrocytes group and ZSCLE treated-infected mice with 106P. chabaudi-parasitized erythrocytes group. The results showed a remarkable reduction of parasitemia level and notable reverse of the anemic picture among ZSCLE treated-infected mice. The effects of ZSCLE on the liver functions enzymes and on the histopathological pictures of liver were significant. It could be concluded that Z. spina-christi leaf extracts have a protective role against Plasmodium infection that also marked through significant restoration of hepatic oxidative markers.