scholarly journals Metabolomic analysis of protozoan parasites

2011 ◽  
Vol 32 (4) ◽  
pp. 144
Author(s):  
Eleanor Saunders ◽  
David De Souza ◽  
James McRae ◽  
Vladimir Likic ◽  
Malcolm McConville
Keyword(s):  
Drug Targets ◽  
Metabolic Networks ◽  
Host Responses ◽  
Drug Resistant ◽  
Metabolomic Analysis ◽  
Protozoan Parasites ◽  
Metabolic Capacity ◽  
Omics Technologies ◽  
Potential Drug Targets ◽  
Drug Resistant Parasite

Protozoan parasites cause a number of important diseases in humans, including malaria, African trypanosomiasis, Chagas disease and the leishmaniases. Current therapeutics for these diseases are limited and their effectiveness is being further undermined by the emergence of drug-resistant parasite strains. Parasite genome sequencing projects have provided new insights into the metabolic capacity of these pathogens and have highlighted potential drug targets. However, these genome-based reconstructions of metabolic networks are incomplete and we still have only a limited understanding of the metabolic requirements of these pathogens during infection. Metabolomics has emerged as a powerful new tool for investigating parasite metabolism and host responses, complementing more established omics technologies as well as being useful as a stand-alone technique.

scholarly journals Transcriptional and proteomic insights into the host response in fatal COVID-19 cases

2020 ◽  
Vol 117 (45) ◽  
pp. 28336-28343 ◽  
Author(s):  
Meng Wu ◽  
Yaobing Chen ◽  
Han Xia ◽  
Changli Wang ◽  
Chin Yee Tan ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Host Response ◽  
Drug Targets ◽  
Potential Role ◽  
Host Responses ◽  
Human Lung Tissue ◽  
Proteomics Analysis ◽  
Global Pandemic ◽  
A Site ◽  
Potential Drug Targets

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

scholarly journals Identification of a Novel Therapeutic Target against XDR Salmonella Typhi H58 Using Genomics Driven Approach Followed Up by Natural Products Virtual Screening

2021 ◽  
Vol 9 (12) ◽  
pp. 2512
Author(s):  
Khurshid Jalal ◽  
Kanwal Khan ◽  
Muhammad Hassam ◽  
Muhammad Naseer Abbas ◽  
Reaz Uddin ◽  
...  
Keyword(s):  
Typhoid Fever ◽  
Drug Targets ◽  
Salmonella Typhi ◽  
Drug Resistant ◽  
Acid Biosynthesis ◽  
New Drug ◽  
Subtractive Genomics ◽  
Colanic Acid ◽  
Novel Drug ◽  
Potential Drug Targets

Typhoid fever is caused by a pathogenic, rod-shaped, flagellated, and Gram-negative bacterium known as Salmonella Typhi. It features a polysaccharide capsule that acts as a virulence factor and deceives the host immune system by protecting phagocytosis. Typhoid fever remains a major health concern in low and middle-income countries, with an estimated death rate of ~200,000 per annum. However, the situation is exacerbated by the emergence of the extensively drug-resistant (XDR) strain designated as H58 of S. Typhi. The emergence of the XDR strain is alarming, and it poses serious threats to public health due to the failure of the current therapeutic regimen. A relatively newer computational method called subtractive genomics analyses has been widely applied to discover novel and new drug targets against pathogens, particularly drug-resistant ones. The method involves the gradual reduction of the complete proteome of the pathogen, leading to few potential and novel drug targets. Thus, in the current study, a subtractive genomics approach was applied against the Salmonella XDR strain to identify potential drug targets. The current study predicted four prioritized proteins (i.e., Colanic acid biosynthesis acetyltransferase wcaB, Shikimate dehydrogenase aroE, multidrug efflux RND transporter permease subunit MdtC, and pantothenate synthetase panC) as potential drug targets. Though few of the prioritized proteins are treated in the literature as the established drug targets against other pathogenic bacteria, these drug targets are identified here for the first time against S. Typhi (i.e., S. Typhi XDR). The current study aimed at drawing attention to new drug targets against S. Typhi that remain largely unexplored. One of the prioritized drug targets, i.e., Colanic acid biosynthesis acetyltransferase, was predicted as a unique, new drug target against S. Typhi XDR. Therefore, the Colanic acid was further explored using structure-based techniques. Additionally, ~1000 natural compounds were docked with Colanic acid biosynthesis acetyltransferase, resulting in the prediction of seven compounds as potential lead candidates against the S. Typhi XDR strain. The ADMET properties and binding energies via the docking program of these seven compounds characterized them as novel drug candidates. They may potentially be used for the development of future drugs in the treatment of Typhoid fever.

Potential Drug Targets Identification against Clostridioides difficile (CD) and Characterization of Indispensable Proteins by a Subtractive Genomics Approach Followed by Virtual Screening

2021 ◽  
Vol 18 ◽  
Author(s):  
Reaz Uddin ◽  
Alina Arif
Keyword(s):  
Drug Targets ◽  
Drug Resistant ◽  
Potential Drug ◽  
Drug Candidates ◽  
Subtractive Genomics ◽  
Clostridioides Difficile ◽  
Subtractive Genomics Approach ◽  
Novel Drug ◽  
Potential Drug Targets ◽  
Novel Drug Targets

Background: Clostridioides difficile (CD) is a multi-drug resistant, enteric pathogenic bacterium. The CD associated infections are the leading cause of nosocomial diarrhea that can further lead to pseudomembranous colitis up to a toxic mega-colon or sepsis with greater mortality and morbidity risks. The CD infection possess higher rates of recurrence due to its greater resistance against antibiotics. Considering its higher rates of recurrence, it has become a major burden on the healthcare facilities. Therefore, there is a dire need to identify novel drug targets to combat with the antibiotic resistance of Clostridioides difficile. Objective: To identify and propose new and novel drug targets against the Clostridioides difficile. Methods: In the current study, a computational subtractive genomics approach was applied to obtain a set of potential drug targets that exists in the multi-drug resistant strain of Clostridioides difficile. Here, the uncharacterized proteins were studied as potential drug targets. The methodology involved several bioinformatics databases and tools. The druggable proteins sequences were retrieved based on non-homology with host proteome and essentiality for the survival of the pathogen. The uncharacterized proteins were functionally characterized using different computational tools and sub-cellular localization was also predicted. The metabolic pathways were analyzed using KEGG database. Eventually, the druggable proteome has been fetched using sequence similarity with the already available drug targets present in DrugBank database. These druggable proteins were further explored for the structural details to identify drug candidates. Results : A priority list of potential drug targets was provided with the help of the applied method on complete proteome set of the C. difficile. Moreover, the drug like compounds have been screened against the potential drug targets to prioritize potential drug candidates. To facilitate the need for drug targets and therapies, the study proposed five potential protein drug targets out of which three proposed drug targets were subjected to homology modeling to explore their structural and functional activities. Conclusion: In conclusion, we proposed three unique, unexplored drug targets against C. difficile. The structure-based methods were applied and resulted in a list of top scoring compounds as potential inhibitors to proposed drug targets.

scholarly journals Decreased glutamate transport in acivicin resistant Leishmania tarentolae

2021 ◽  
Vol 15 (12) ◽  
pp. e0010046
Author(s):  
Gaétan Roy ◽  
Arijit Bhattacharya ◽  
Philippe Leprohon ◽  
Marc Ouellette
Keyword(s):  
Drug Targets ◽  
Glutamate Transporter ◽  
Resistant Mutant ◽  
Glutamate Transport ◽  
Amino Acid Transporters ◽  
Wild Type ◽  
Protozoan Parasites ◽  
Leishmania Tarentolae ◽  
Gene Coding ◽  
Potential Drug Targets

Studies of drug resistance in the protozoan parasites of the genus Leishmania have been helpful in revealing biochemical pathways as potential drug targets. The chlorinated glutamine analogue acivicin has shown good activity against Leishmania cells and was shown to target several enzymes containing amidotransferase domains. We selected a Leishmania tarentolae clone for acivicin resistance. The genome of this resistant strain was sequenced and the gene coding for the amidotransferase domain-containing GMP synthase was found to be amplified. Episomal expression of this gene in wild-type L. tarentolae revealed a modest role in acivicin resistance. The most prominent defect observed in the resistant mutant was reduced uptake of glutamate, and through competition experiments we determined that glutamate and acivicin, but not glutamine, share the same transporter. Several amino acid transporters (AATs) were either deleted or mutated in the resistant cells. Some contributed to the acivicin resistance phenotype although none corresponded to the main glutamate transporter. Through sequence analysis one AAT on chromosome 22 corresponded to the main glutamate transporter. Episomal expression of the gene coding for this transporter in the resistant mutant restored glutamate transport and acivicin susceptibility. Its genetic knockout led to reduced glutamate transport and acivicin resistance. We propose that acivicin binds covalently to this transporter and as such leads to decreased transport of glutamate and acivicin thus leading to acivicin resistance.

scholarly journals Identification of Missing Carbon Fixation Enzymes as Potential Drug Targets in Mycobacterium Tuberculosis

2018 ◽  
Vol 15 (3) ◽  
Author(s):  
Amit Katiyar ◽  
Harpreet Singh ◽  
Krishna Kant Azad
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Target ◽  
Drug Targets ◽  
Metabolic Networks ◽  
Carbon Fixation ◽  
New Drugs ◽  
Metabolic Adaptation ◽  
Potential Drug ◽  
Genes Encoding ◽  
Potential Drug Targets

Abstract Metabolic adaptation to the host environment has been recognized as an essential mechanism of pathogenicity and the growth of Mycobacterium tuberculosis (Mtb) in the lungs for decades. The Mtb uses CO2 as a source of carbon during the dormant or non-replicative state. However, there is a lack of biochemical knowledge of its metabolic networks. In this study, we investigated the CO2 fixation pathways (such as ko00710 and ko00720) most likely involved in the energy production and conversion of CO2 in Mtb. Extensive pathway evaluation of 23 completely sequenced strains of Mtb confirmed the existence of a complete list of genes encoding the relevant enzymes of the reductive tricarboxylic acid (rTCA) cycle. This provides the evidence that an rTCA cycle may function to fix CO2 in this bacterium. We also proposed that as CO2 is plentiful in the lungs, inhibition of CO2 fixation pathways (by targeting the relevant CO2 fixation enzymes) could be used in the expansion of new drugs against the dormant Mtb. In support of the suggested hypothesis, the CO2 fixation enzymes were confirmed as a potential drug target by analyzing a number of attributes necessary to be a good bacterial target.

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