Some Scaffolds as Anti-leishmanial Agents: An Review

: Leishmaniasis is a parasitic infectious neglected tropical disease transmitted to humans by the parasites of Leishmania species. Mainly three types of leishmaniasis cases such as visceral (VL), cutaneous (CL) and mucocutaneous leishmaniasis are usually observed. In many western countries, almost 700,000 to 1million peoples are suffering from leishmaniasis and it is estimated that around 26000 to 65000 deaths occurs annually. For its treatment few drugs are available however none of them are ideal to treat leishmaniasis due to long treatment, discomfort mode of administration, risk of high level toxicity, high resistance against etc. Hence so many patients are unable to take complete treatment due to the high drug resistance. The present review will focus on antileishmanial activity of reported derivatives of betacarboline, chalcone, azole, quinoline, quinazoline, benzimidazole, benzadiazapine, thiaazoles, semicarbazone and hydontoin analogues. We believe that this present study will helpful to researcher to design new antileishmanial agents.

Download Full-text

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Parasites & Vectors ◽

10.1186/s13071-020-04397-4 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Zhiwan Zheng ◽

Jianping Chen ◽

Guangxu Ma ◽

Abhay R. Satoskar ◽

Jiao Li

Keyword(s):

Drug Resistance ◽

Protein Expression ◽

Leishmania Donovani ◽

Molecular Mechanisms ◽

Copy Number Variations ◽

Tropical Disease ◽

Effective Control ◽

Resistance Testing ◽

Neglected Tropical Disease ◽

Protein Coding

Abstract Background Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the effective control and elimination programme of this neglected tropical disease. Methods In this work, we conducted drug-resistance testing, whole genome resequencing and proteome profiling for a recently reported clinical isolate with supposed drug resistance (HCZ), and two reference sensitive strains (DD8 and 9044) of Leishmania donovani, to explore molecular mechanisms underlying drug resistance in this parasite. Results With reference to DD8 and 9044 strains, HCZ isolate showed higher-level virulence and clear resistance to antimonials in promastigote culture, infected macrophages and animal experiment. Pairwise genomic comparisons revealed genetic variations (86 copy number variations, 271 frameshift mutations in protein-coding genes and two site mutations in non-coding genes) in HCZ isolate that were absent from the reference sensitive strains. Proteomic analysis indicated different protein expression between HCZ isolate and reference strains, including 69 exclusively detected proteins and 82 consistently down-/upregulated molecules in the HCZ isolate. Integrative analysis showed linkage of 12 genomic variations (gene duplication, insertion and deletion) and their protein expression changes in HCZ isolate, which might be associated with pathogenic and antimony-resistant phenotype. Functional annotation analyses further indicated that molecules involved in nucleotide-binding, fatty acid metabolism, oxidation-reduction and transport might play a role in host-parasite interaction and drug-resistance. Conclusions This comprehensive integrative work provided novel insights into the genetic basis underlying virulence and resistance, suggesting new aspects to be investigated for a better intervention against L. donovani and associated diseases.

Download Full-text

New approaches for understanding mechanisms of drug resistance in schistosomes

Parasitology ◽

10.1017/s0031182013000231 ◽

2013 ◽

Vol 140 (12) ◽

pp. 1534-1546 ◽

Cited By ~ 69

Author(s):

ROBERT M. GREENBERG

Keyword(s):

Drug Resistance ◽

Mode Of Action ◽

Tropical Disease ◽

Neglected Tropical Disease ◽

Single Drug ◽

New Approaches ◽

And Control ◽

Emergence Of Resistance

SUMMARYSchistosomes are parasitic flatworms that cause schistosomiasis, a neglected tropical disease that affects hundreds of millions worldwide. Treatment and control of schistosomiasis relies almost entirely on the single drug praziquantel (PZQ), making the prospect of emerging drug resistance particularly worrisome. This review will survey reports of PZQ (and other drug) resistance in schistosomes and other platyhelminths, and explore mechanisms by which drug resistance might develop. Newer genomic and post-genomic strategies that offer the promise of better understanding of how drug resistance might arise in these organisms will be discussed. These approaches could also lead to insights into the mode of action of these drugs and potentially provide markers for monitoring the emergence of resistance.

Download Full-text

AL 4565 ALLOY

Alloy Digest ◽

10.31399/asm.ad.ss0906 ◽

2004 ◽

Vol 53 (8) ◽

Keyword(s):

Fracture Toughness ◽

Corrosion Resistance ◽

High Temperature ◽

High Resistance ◽

Flue Gas ◽

Heat Treating ◽

Flue Gas Desulfurization ◽

High Nitrogen ◽

Temperature Performance ◽

High Level

Abstract AL 4565 alloy has a high level of austenitizers, which provides the microstructure with a high resistance to sigma formation during welding. The high nitrogen also gives the alloy superior strength among the austenitics. Applications include flue gas desulfurization and handling seawater. This datasheet provides information on composition, physical properties, hardness, elasticity, and tensile properties as well as fracture toughness. It also includes information on high temperature performance and corrosion resistance as well as heat treating and joining. Filing Code: SS-906. Producer or source: Allegheny Ludlum Corporation.

Download Full-text

Development of Novel Therapeutics for Neglected Tropical Disease Leishmaniasis

10.21236/ada637013 ◽

2015 ◽

Author(s):

Abhay Satoskar

Keyword(s):

Tropical Disease ◽

Neglected Tropical Disease ◽

Novel Therapeutics

Download Full-text

In Vitro Effect of Chlorquine and Picroliv on Plasmodium Berghei Induced Alterations in the Activity of Adenosine Triphosphatase, Aryl Hyrocarbon Hydroxylase Enzymes and Malondialdehyde in spleen Explant Culture

Infectious Disorders - Drug Targets ◽

10.2174/1871526520666200630124419 ◽

2020 ◽

Vol 20 ◽

Author(s):

Anchal Trivedi ◽

Aparna Misra ◽

Esha Sarkar ◽

Anil K. Balapure

Keyword(s):

Drug Resistance ◽

Plasmodium Berghei ◽

Adenosine Triphosphatase ◽

Explant Culture ◽

Need To Evaluate ◽

Mda Content ◽

High Level ◽

Vitro Effect ◽

Positive Effect

Background: In recent years, great progress has been made in reducing the high level of malaria suffering worldwide. There is a great need to evaluate drug resistance reversers and consider new medicines against malaria. There are many approaches to the development of antimalarial drugs. Specific concerns must be taken in to account in these approaches, in particular there requirement for very in expensive and simple use of new therapies and the need to limit drug discovery expenses. Important ongoing efforts are the optimisation of treatment with available medications, including the use of combination therapy. The production of analogs of known agents and the identification of natural products, the use of compounds originally developed against other diseases, the assessment of overcoming drug resistance and the consideration of new therapeutic targets. Liver and spleen are the important organs which are directly associated with malarial complications. Aim: An analysis the Activity of Adenosine Triphosphatase, Aryl Hyrocarbon Hydroxylase Enzymes and Malondialdehyde in spleen Explant Culture. Objective: To determine in-Vitro Effect of Chlorquine and Picroliv on Plasmodium Berghei Induced Alterations in the Activity of Adenosine Triphosphatase, Aryl Hyrocarbon Hydroxylase Enzymes and Malondialdehyde in spleen Explant Culture. Material and method: 1-Histological preparation of spleen explants for paraplast embedding 2-Biochemicalstudies (Enzymes (Atpase, ALP&GST) and the level of protein, Malondialdehyde (MDA). Result: Splenomegalyis one of the three main diagnostic parameters of malaria infection besides fever and anaemia. Many enzymes present in the liver and spleen may also be altered or liberated under different pathological conditions. Enzymes (ATPase, ALP&GST) and the level of protein, Malondialdehyde (MDA) content was found to increase in the liver and spleen explants during malarial infection. In the liver and spleen derived from parasitized CQ treated animals, the activity of all the above enzymes (ATPase, ALP&GST) and the level of protein & MDA of liver/spleen reversed towards the normal for all the 4or3 days of incubations. Picroliv efficacy decreased with the increment of parasitaemia and at 60%parasitaemia. Conclusion: Alkalinephosphatase (ALP) was found to increase with increasing parasitaemia. After the addition of Picroliv to the medium, a decrement in the activity was observed up to day 4 of culture.A similar positive effect of Picroliv was observed on the ATPase and ALP activity of spleen explants.DNA and protein contents also increased in the parasitized liver cultured in the presence of picroliv.On the contrary, in the spleen explants DNA, protein and MDA content were found to decrease after Picroliv supplementation to the culture medium.

Download Full-text

The Search for a Schistosomiasis Vaccine: Australia’s Contribution

Vaccines ◽

10.3390/vaccines9080872 ◽

2021 ◽

Vol 9 (8) ◽

pp. 872

Author(s):

Donald P. McManus

Keyword(s):

Public Health ◽

Drug Resistance ◽

Sub Saharan Africa ◽

Effective Vaccine ◽

Neglected Tropical Disease ◽

Vaccine Research ◽

Health Measures ◽

Leading Role ◽

Invaluable Tool ◽

Sub Saharan

Schistosomiasis, a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, results in considerable human morbidity in sub-Saharan Africa, in particular, but also parts of the Middle East, South America, and Southeast Asia. The anti-schistosome drug praziquantel is efficacious and safe against the adult parasites of all Schistosoma species infecting humans; however, it does not prevent reinfection and the development of drug resistance is a constant concern. The need to develop an effective vaccine is of great importance if the health of many in the developing world is to be improved. Indeed, vaccination, in combination with other public health measures, can provide an invaluable tool to achieve lasting control, leading to schistosomiasis elimination. Australia has played a leading role in schistosomiasis vaccine research over many years and this review presents an overview of some of the significant contributions made by Australian scientists in this important area.

Download Full-text

Evaluating the potential impact of interruptions to neglected tropical disease programmes due to COVID-19

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1093/trstmh/trab023 ◽

2021 ◽

Vol 115 (3) ◽

pp. 201-204

Author(s):

T Déirdre Hollingsworth ◽

Pauline Mwinzi ◽

Andreia Vasconcelos ◽

Sake J de Vlas

Keyword(s):

Tropical Disease ◽

Neglected Tropical Disease ◽

Potential Impact

Download Full-text

Microevolution within ST11 group Clostridioides difficile isolates through mobile genetic elements based on complete genome sequencing

BMC Genomics ◽

10.1186/s12864-019-6184-1 ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Yuan Wu ◽

Lin Yang ◽

Wen-Ge Li ◽

Wen Zhu Zhang ◽

Zheng Jie Liu ◽

...

Keyword(s):

Drug Resistance ◽

Resistance Genes ◽

Point Mutations ◽

Evolutionary Process ◽

Mobile Genetic Elements ◽

Genetic Elements ◽

Clostridioides Difficile ◽

Hospitalized Elderly ◽

Great Heterogeneity ◽

High Level

Abstract Background Clade 5 Clostridioides difficile diverges significantly from the other clades and is therefore, attracting increasing attention due its great heterogeneity. In this study, we used third-generation sequencing techniques to sequence the complete whole genomes of three ST11 C. difficile isolates, RT078 and another two new ribotypes (RTs), obtained from three independent hospitalized elderly patients undergoing antibiotics treatment. Mobile genetic elements (MGEs), antibiotic-resistance, drug resistance genes, and virulent-related genes were analyzed and compared within these three isolates. Results Isolates 10,010 and 12,038 carried a distinct deletion in tcdA compared with isolate 21,062. Furthermore, all three isolates had identical deletions and point-mutations in tcdC, which was once thought to be a unique characteristic of RT078. Isolate 21,062 (RT078) had a unique plasmid, different numbers of transposons and genetic organization, and harboring special CRISPR spacers. All three isolates retained high-level sensitivity to 11 drugs and isolate 21,062 (RT078) carried distinct drug-resistance genes and loss of numerous flagellum-related genes. Conclusions We concluded that capillary electrophoresis based PCR-ribotyping is important for confirming RT078. Furthermore, RT078 isolates displayed specific MGEs, indicating an independent evolutionary process. In the further study, we could testify these findings with more RT078 isolates of divergent origins.

Download Full-text