Material-Microbe Interfaces for Solar-Driven CO2 Bioelectrosynthesis.

Sustainable production of solar-based chemicals is possible by mimicking the natural photosynthetic mechanism. To realize the full potential of solar-to-chemical production, the artificial means of photosynthesis and the biological approach should complement each other. The recently developed hybrid microbe-metal interface combines an inorganic, semiconducting light-harvester material with efficient and simple microorganisms, resulting in a novel metal-microbe interface that helps the microbes to capture energy directly from sunlight. This solar energy is then used for sustainable biosynthesis of chemicals from CO2. This review discusses various approaches to improve the electron uptake by microbes at the bioinorganic interface, especially self-photosensitized microbial systems and integrated water splitting biosynthetic systems, with emphasis on CO2 bioelectrosynthesis.

Photosensitization of electro-active microbes for solar assisted carbon dioxide transformation.

Tandem bio-inorganic platform by combining efficient light harvesting properties of nano-inorganic semiconductor cadmium sulfide (CdS) with biocatalytic ability of electro-active bacteria (EAB) towards carbon dioxide (CO2) conversion is reported. Sulfur was obtained from either cysteine (EAB-Cys-CdS) or hydrogen sulfide (EAB-H2S-CdS) and experiments were carried out under similar conditions. Anchoring of the nano CdS cluster on the microbe surface was confirmed using electronic microscope. Bio-inorganic hybrid system was able to produce single and multi-carbon compounds from CO2 in visible spectrum (λ > 400 nm). Though, acetic acid was dominant (EAB-Cys-CdS, 1.46 g/l and EAB-H2S-CdS, 1.55 g/l) in both the microbe-CdS hybrids, its concentration as well as product slate varied significantly. EAB-H2S-CdS produced hexanoic acid and less methanol fraction, while the EAB-Cys-CdS produced no hexanoic acid along with almost double the concentration of methanol. Due to easy harvesting process, this bio-inorganic hybrid represents unique sustainable approach for solar-to-chemical production via CO2 transformation.

Long-term operation of electro-biocatalytic reactor for carbon dioxide transformation into organic molecules.

Electro-biocatalytic reactor was operated using selectively enriched mixed culture biofilm for about 320 days with CO2/bicarbonate as C-source. Biocathode consumed higher current (-16.2 ±â€¯0.3 A/m2) for bicarbonate transformation yielding high product synthesis (0.74 g/l/day) compared to CO2 (-9.5 ±â€¯2.8 A/m2; 0.41 g/l/day). Product slate includes butanol and butyric acid when CO2 gets transformed but propionic acid replaced both when bicarbonate gets transformed. Based on electroanalysis, the electron transfer might be H2 mediated along with direct transfer under bicarbonate turnover conditions, while it was restricted to direct under CO2. Efficiency and stability of biofilm was tested by removing the planktonic cells, and also confirmed in terms of Coulombic (85-97%) and carbon conversion efficiencies (42-48%) along with production rate (1.2-1.7 kg/m2 electrode) using bicarbonate as substrate. Selective enrichment of microbes and their growth as biofilm along with soluble CO2 have helped in efficient transformation of CO2 up to C4 organic molecules.

Bio-electrochemical system (BES) as an innovative approach for sustainable waste management in petroleum industry.

Petroleum industry is one of the largest and fast growing industries due to the ever increasing global energy demands. Petroleum refinery produces huge quantities of wastes like oily sludge, wastewater, volatile organic compounds, waste catalyst, heavy metals, etc., because of its high capacity and continuous operation of many units. Major challenge to this industry is to manage the huge quantities of waste generated from different processes due to the complexity of waste as well as changing stringent environmental regulations. To decrease the energy loss for treatment and also to conserve the energy stored in the chemical bonds of these waste organics, bio-electrochemical system (BES) may be an efficient tool that reduce the economics of waste disposal by transforming the waste into energy pool. The present review discusses about the feasibility of using BES as a potential option for harnessing energy from different waste generated from petroleum refineries.

Electro-biocatalytic conversion of carbon dioxide to alcohols using gas diffusion electrode.

Impact of gas diffusion electrodes (GDEs) was evaluated in enhancing the CO2 bio-availability for its transformation to C4-organics, especially to alcohols using selective mixed culture. Observed current density was more stable (9-11 A/m2) than submerged experiments reported and significantly varied with pH and respective CO2 solubility. Uncontrolled operating pH (starting with 8.0) showed its impact on shifting/triggering alternate metabolic pathways to increase the carbon length (butyric acid) as well as producing more reduced end products, i.e. alcohols. During the experiments, CO2 was transformed initially to a mixture of volatile fatty acids dominated with formic and acetic acids, and upon their accumulation, ethanol and butanol production was triggered. Overall, 21 g/l of alcohols and 13 g/l of organic acids were accumulated in 90 days with a coulombic efficiency (CE) of 49%. Ethanol and butanol occupied respectively about 45% and 16% of total products, indicating larger potential of this technology.

Aquatic weeds as the next generation feedstock for sustainable bioenergy production.

Increasing oil prices and depletion of existing fossil fuel reserves, combined with the continuous rise in greenhouse gas emissions, have fostered the need to explore and develop new renewable bioenergy feedstocks that do not require arable land and freshwater resources. In this regard, prolific biomass growth of invasive aquatic weeds in wastewater has gained much attention in recent years in utilizing them as a potential feedstock for bioenergy production. Aquatic weeds have an exceptionally higher reproduction rates and are rich in cellulose and hemicellulose with a very low lignin content that makes them an efficient next generation biofuel crop. Considering their potential as an effective phytoremediators, this review presents a model of integrated aquatic biomass production, phytoremediation and bioenergy generation to reduce the land, fresh water and fertilizer usage for sustainable and economical bioenergy.

Correlation between in vitro and in vivo antimalarial activity of compounds using CQ-sensitive and CQ-resistant strains of Plasmodium falciparum and CQ-resistant strain of P. yoelii.

Present efforts have been made to establish a correlation between in vitro and in vivo antimalarial activity using MIC, IC50 and IC90 values against CQ-sensitive (3D7) and CQ-resistant (K1) strains of Plasmodium falciparum and in vivo activity against Plasmodium yoelii. The method of discriminant function analysis (DFA) was applied to analyze the data. It was observed that in vitro IC90 values against both 3D7 and K1 strains (p < 0.001) have strong correlation with in vivo curative activity. The respective IC50 and IC90 values of compounds, which cured mice (i.e., animals did not show recrudescence of parasitemia even after 60 days posttreatment), ranged between 3 and 14 nM and 14 and 186 nM against 3D7 and between 9 and 65 nM and 24 and 359 nM against the K1 strain of P. falciparum. Whereas the IC50 and IC90 values of compounds which exhibited in vivo suppressive activity in mice ranged between 10 and 307 nm and 61 and >965 nM, respectively, against 3D7 and 75 and >806 nm and 241 and >1232 nM against the K1 strain of P. falciparum. The findings suggest that IC90 values against both 3D7 and K1 strains (p < 0.02) are the main contributors for the prediction of in vivo curative activity of a new molecule. Apart from this, a reasonable correlation between MIC and IC50 values of compounds has also been established.

Broad spectrum anti-infective properties of benzisothiazolones and the parallels in their anti-bacterial and anti-fungal effects.

Various mono- and bis-benzisothiazolone derivatives were synthesized and screened against different strains of bacteria and fungi in order to understand the effect of multiple electrophilic sulfur atoms and substitution pattern in the immediate vicinity of reactive sulfur. Staphyllococcus aureus-ATCC 7000699, MRSA and S. aureus-ATCC 29213 (Quality Control strain) were more susceptible to this class of compounds, and the most potent derivative 1.15 had MIC50 of 0.4µg/mL (cf. Gentamicin=0.78µg/mL). CLogP value, optimally in the range of 2.5-3.5, appeared to contribute more to the activity than the steric and electronic effects of groups attached at nitrogen. By and large, their anti-fungal activities also followed a similar trend with respect to the structure and CLogP values. The best potency of IC50=0.1µg/mL was shown by N-benzyl derivative (1.7) against Aspergillus fumigatus; it was also potent against Candida albicans, Cryptococcus neoformans, Sporothrix schenckii, and Candida parapsilosis with IC50 values ranging from 0.4 to 1.3µg/mL. Preliminary studies also showed that this class of compounds have the ability to target malaria parasite with IC50 values in low micromolar range, and improvement of selectivity is possible through structure optimization.

Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy.

A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

Immunoprotective effect of lentinan in combination with miltefosine on Leishmania-infected J-774A.1 macrophages.

Rejuvenation of deteriorated host immune functions is imperative for successful annihilation of Leishmania parasites. The use of immunomodulatory agents may have several advantages as they conquer immunosuppression and, when given in combination, improve current therapeutic regimens. We herein investigated the immunostimulatory potency of a ß-glucan, lentinan either alone or in combination with short dose of standard drug, miltefosine on Leishmania-infected J-774A.1 macrophages. Our study shows that infected macrophages when stimulated with 2.5 µg/mL and above concentrations of lentinan secreted significant amount of host-protective molecules. The in vitro interaction between lentinan and miltefosine showed some synergy (mean sum of fractional inhibitory concentration [mean ∑FIC] 0.87) at IC50 level. Lentinan (2.5 µg/mL) plus low-dose miltefosine (2 µM) displayed heightened level of pro-inflammatory cytokines, IL-12 (13.6-fold) and TNF-α (6.8-fold) along with nitric oxide (7.2-fold higher) when compared with infected control. In combination group, we also observed remarkably (P<.001) suppressed levels of anti-inflammatory cytokines, IL-10 and TGF-ß, than that of untreated macrophages. Additionally, in comparison with infected group, we observed significant induction in phagocytic activity of macrophages in combination with treated group. Collectively, these findings emphasize the immunostimulatory effect of lentinan alone and in combination with low dose of miltefosine against Leishmania donovani.

Arteether resistance reversal by ketoconazole/fluconazole in rodent malaria parasite Plasmodium vinckei.

Artemisinin and its derivative arteether (ART) are fast acting antimalarial drugs against chloroquine-resistant. There are several partner drugs that are identified as a potential drug for artemisinin combination therapy (ACT) to develop as the antimalarial drug. Limited studies have been carried out in ART drug combination that may have more promising as ACT for resistant Plasmodium parasite. Here, we are the first to show the ART drug resistance reversal in Plasmodium vinckei by using antifungal azole compounds ketoconazole (KTZ) and fluconazole (FCZ). Our previous study has shown that higher antioxidant enzyme, glutathione, and less hemozoin may be correlated with ART resistance in P. vinckei (PvAR). We further hypothesized that glutathione and heme catabolism may be interfered by KTZ and FCZ, resulting in an increased efficacy of ART in PvAR parasite. The results of present study demonstrate synergetic effect of KTZ and FCZ against PvAR parasite, since none of the mice developed infection up to day 10 after combination with ART. These results further showed that ED90 of ART was reduced from 17.23 to 2.19 and 2.56 mg/kg when used in combination with KTZ and FCZ, respectively. Resultant, activity enhancement index (AEI) of ART is significantly increased to 8.60 and 6.73 with partner agents. These studies propose the possibility of ART drug combination that may be helpful in prolonging the life of drug and a promising lead to reduce the chance of resistance development of artemisinin and its derivative.

Hydrothermal conversion of lignin to substituted phenols and aromatic ethers.

Hydrothermal liquefaction of lignin was performed using methanol and ethanol at various temperatures (200, 250 and 280°C) and residence times of 15, 30 and 45min. Maximum liquid product yield (85%) was observed at 200°C and 15min residence time using methanol. Increase in temperature was seen to decrease the liquid products yield. With increase in residence time, liquid yields first increased and then decreased. FTIR and (1)H NMR showed the presence of substituted phenols and aromatic ethers in liquid products and breakage of ß-O-4 or/and α-O-4 ether bonds present in lignin during hydrothermal liquefaction was confirmed through FTIR of bio-residue. In comparison to the existing literature information, higher lignin conversion to liquid products and maximum carbon conversion (72%) was achieved in this study.

A natural product inspired hybrid approach towards the synthesis of novel pentamidine based scaffolds as potential anti-parasitic agents.

A natural product inspired molecular hybridization approach led us to a series of novel pentamidine based pyrimidine and chalcone scaffolds. All the hybrids were evaluated for their anti-leishmanial potential. Most of the screened compounds have showed significant in vitro anti-leishmanial activity with less cytotoxicity in comparison to the standard drugs (pentamidine, sodium stibogluconate, and miltefosine). Additionally, anti-malarial screening of these compounds was also done and four compounds have shown superior activity against chloroquine resistance strain (K1) of Plasmodium falciparum.

Synthesis and antimalarial activity of 3,3-spiroanellated 5,6-disubstituted 1,2,4-trioxanes.

Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound of the series (compound 25) provided 100% protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, ß-arteether provided 100 and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. Compound 25 displayed a similar in vitro pharmacokinetic profile to that of reference drug ß-arteether. The activity results demonstrated the importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.

Coumarin-trioxane hybrids: synthesis and evaluation as a new class of antimalarial scaffolds.

First synthesis of novel coumarin-trioxane hybrids is reported. The synthesis was achieved via condensation of ß-hydroxyhydroperoxides with coumarinic-aldehydes in presence of p-toluenesulfonic acid in good yields and the novel hybrids were evaluated for their antimalarial activity both in vitro and in vivo.

Plasmodium vinckei: infectivity of arteether-sensitive and arteether-resistant parasites in different strains of mice.

Malaria is one of the most lethal parasitic infections in the world. The lethality of the parasite depends on the rate of multiplication of the parasite within host erythrocytes. Different strains of the malaria parasite often respond in a different way to the same strain of mice or vice versa. In the present study, we investigated the course of infection of the arteether-sensitive and arteether-resistant Plasmodium vinckei parasites in Swiss albino AKR (inbred) and AJ (outbred) mice. The higher parasite burden and mortality were observed in the sensitive parasite-infected mice, whereas the infection with the resistant parasite was non-lethal. Resistant parasite-infected mice developed a moderate level of parasitemia that decreased gradually throughout the infection. The microscopic examination suggests that the resistant parasite invades reticulocytes more efficiently than normocytes, regardless of the mouse strain examined. Since the reticulocytes are rare in blood circulation, it limits the increase in parasite proliferations, while arteether-sensitive parasites can invade both mature normocytes and reticulocytes, resulting in the mortality of the mice. However, treatment with phenylhydrazine in Swiss mice results in reticulocytosis, which transforms the non-lethal resistant parasites to produce lethal infections. Our findings demonstrate that the characteristic response during infections with the arteether-resistant strain is dependent on the availability of reticulocytes in peripheral blood circulation. We can use this model for identifying the interaction between host and artemisinin derivative-resistant parasites.

In vitro activities of new 2-substituted quinolines against Leishmania donovani.

A series of 9 quinolines and 18 styrylquinolines was evaluated for the drugs' in vitro antileishmanial activities and cytotoxicities. The 7-aroylstyrylquinoline scaffold appeared to be the most promising one, with the most interesting compound, no. 35, exhibiting a 50% inhibitory concentration (IC(50)) of 1.2 µM and a selectivity index value of 121.5. Compound 35 was 10-fold and 8-fold more active than miltefosine and sitamaquine, the reference compounds, with selectivity indexes 607-fold and 60-fold higher, respectively.

Implication of intracellular glutathione and its related enzymes on resistance of malaria parasites to the antimalarial drug arteether.

The control of malaria has been complicated by the increasing resistance of malarial parasites to multiple drugs. However, artemisinin-based drugs offer hope in the fight against drug-resistant parasites. The mode of action of these drugs remains unclear, but evidence suggests a role for free radicals in their mechanism of action. In this study, we examined the relationship between the intracellular levels of glutathione (GSH) and antioxidant enzymes and resistance to the artemisinin-based drug arteether in experimentally selected arteether-resistant Plasmodium vinckei. GSH plays a critical role in the detoxification and protection of cells against oxidative stress. Our comparative studies showed a significant (2.9-fold) increase in the GSH level in arteether-resistant parasites as compared to arteether-sensitive parasites. Simultaneously, significantly increased activities of glutathione reductase, glutathione-S transferase and glucose-6-phosphate dehydrogenase and decreased activity of superoxide dismutase were recorded in resistant parasites; the activity of glutathione peroxidase was comparable in arteether-sensitive and -resistant parasites. Artemisinin derivatives act by generating free radicals and our results indicate that glutathione's antioxidant effects may counteract that drug effect and thereby contribute to the parasites' resistance to arteether and other artemisinin-based antimalarials.

In-vitro culture of Plasmodium falciparum: utility of modified (RPNI) medium for drug-sensitivity studies using SYBR Green I assay.

Studies were carried out to establish the potential of RPNI medium for drug-sensitivity studies using the MSF assay. The drug sensitivity of standard anti-malarials was compared using both the ((3)H) Hypoxanthine incorporation assay and the MSF assay. The media supplements used during the study have been human serum, FBS and ALBUMAX-II. Drug sensitivity of two parasite lines, adapted to grow separately in conventional as well as in RPNI medium was compared to observe the effect of RPNI medium on functional characteristics of the parasite. The results revealed identical IC(50) values of standard anti-malarials obtained by both the ((3)H) Hypoxanthine incorporation assay and the MSF assay and no untoward effect of FBS and ALBUMAX-II could be noticed on the chemo-sensitivity of standard anti-malarials. Apart from this the chemo-sensitive response of parasite line adapted to grow in RPNI medium was observed to be intact. These findings showed that RPNI medium has potential to be used for chemo-sensitivity studies and the MSF assay being more convenient was observed to be most suitable assay for bio evaluation of new molecules.

Synthesis of new 4-aminoquinolines and quinoline-acridine hybrids as antimalarial agents.

Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions, research findings provide considerable support that there is still significant potential to discover new affordable, safe, and efficacious 4-aminoquinoline antimalarials. In present study, new side chain modified 4-aminoquinoline derivatives and quinoline-acridine hybrids were synthesized and evaluated in vitro against NF 54 strain of Plasmodium falciparum. Among the evaluated compounds, compound 17 (MIC=0.125 µg/mL) was equipotent to standard drug CQ (MIC=0.125 µg/mL) and compound 21 (MIC=0.031 µg/mL) was four times more potent than CQ. Compound 17 showed the curative response to all the treated swiss mice infected with CQ-resistant N-67 strain of Plasmodium yoelii at the doses 50 mg/kg and 25 mg/kg for four days by intraperitoneal route and was found to be orally active at the dose of 100 mg/kg for four days. The promising antimalarial potency of compound 17 highlights the significance of exploring the privileged 4-aminoquinoline class for new antimalarials.