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.

Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

2013 ◽  
Author(s):  
Andrew M. Gulick ◽  
Thomas A. Russo ◽  
L. W. Schultz ◽  
Timothy C. Umland
Keyword(s):  
Drug Targets ◽  
Bacterial Infections ◽  
Drug Resistant ◽  
New Drug

scholarly journals Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

2014 ◽  
Author(s):  
Andrew M. Gulick ◽  
Thomas A. Russo ◽  
L. W. Schulz ◽  
Timothy C. Umland
Keyword(s):  
Drug Targets ◽  
Bacterial Infections ◽  
Drug Resistant ◽  
New Drug

scholarly journals Drug-Resistant Salmonella typhi in Pakistan

2019 ◽  
Vol 59 (1) ◽  
pp. 31-33 ◽  
Author(s):  
Christine E. Petrin ◽  
Russell W. Steele ◽  
Elizabeth A. Margolis ◽  
Justin M. Rabon ◽  
Holly Martin ◽  
...  
Keyword(s):  
United States ◽  
Typhoid Fever ◽  
Enteric Fever ◽  
The United States ◽  
Salmonella Typhi ◽  
Antimicrobial Treatment ◽  
Third Generation ◽  
Drug Resistant ◽  
Oral Transmission ◽  
Third Generation Cephalosporins

Enteric fever (formerly typhoid fever) is a bacterial illness caused by fecal-oral transmission of Salmonella typhi or paratyphi. In early 2018, an outbreak of Salmonella typhi resistant to third-generation cephalosporins, ampicillin, ciprofloxacin, trimethroprim-sulfamethoxazole, and chloramphenicol was reported in Pakistan. This strain, termed “extensively resistant typhi,” has infected more than 5000 patients in endemic areas of South Asia, as well as travelers to and from these areas, including 5 cases in the United States. We present the case of one such child who developed extensively resistant enteric fever during a recent visit to Pakistan and required broader antimicrobial treatment than typically required. Clinicians should be aware that incoming cases of enteric fever may be nonsusceptible to commonly recommended antibiotics and that extensively resistant typhi requires treatment with carbapenems such as meropenem or azithromycin.

scholarly journals Modeling Novel Putative Drugs and Vaccine Candidates against Tick-Borne Pathogens: A Subtractive Proteomics Approach

2020 ◽  
Vol 7 (3) ◽  
pp. 129
Author(s):  
Abid Ali ◽  
Shabir Ahmad ◽  
Abdul Wadood ◽  
Ashfaq U. Rehman ◽  
Hafsa Zahid ◽  
...  
Keyword(s):  
Drug Targets ◽  
Effective Control ◽  
Potential Drug ◽  
Homologous Proteins ◽  
Vaccine Candidates ◽  
Target Proteins ◽  
Subtractive Proteomics ◽  
Novel Drug ◽  
Potential Drug Targets ◽  
Novel Drug Targets

Ticks and tick-borne pathogens (TBPs) continuously causing substantial losses to the public and veterinary health sectors. The identification of putative drug targets and vaccine candidates is crucial to control TBPs. No information has been recorded on designing novel drug targets and vaccine candidates based on proteins. Subtractive proteomics is an in silico approach that utilizes extensive screening for the identification of novel drug targets or vaccine candidates based on the determination of potential target proteins available in a pathogen proteome that may be used effectively to control diseases caused by these infectious agents. The present study aimed to investigate novel drug targets and vaccine candidates by utilizing subtractive proteomics to scan the available proteomes of TBPs and predict essential and non-host homologous proteins required for the survival of these diseases causing agents. Subtractive proteome analysis revealed a list of fifteen essential, non-host homologous, and unique metabolic proteins in the complete proteome of selected pathogens. Among these therapeutic target proteins, three were excluded due to the presence in host gut metagenome, eleven were found to be highly potential drug targets, while only one was found as a potential vaccine candidate against TBPs. The present study may provide a foundation to design potential drug targets and vaccine candidates for the effective control of infections caused by TBPs.

scholarly journals In Silico identification of potential drug targets by subtractive genome analysis of Enterococcus faecium DO

2020 ◽  
Author(s):  
Marwah Karim ◽  
MD Nazrul Islam ◽  
G. M. Nurnabi Azad Jewel
Keyword(s):  
Alcohol Dehydrogenase ◽  
Enterococcus Faecium ◽  
In Silico ◽  
Drug Targets ◽  
3D Structure ◽  
Comparative Genomic ◽  
Therapeutic Drug ◽  
Potential Drug ◽  
Novel Drug ◽  
Potential Drug Targets

AbstractOnce believed to be a commensal bacteria, Enterococcus faecium has recently emerged as an important nosocomial pathogen worldwide. A recent outbreak of E. faecium unrevealed natural and in vitro resistance against a myriad of antibiotics namely ampicillin, gentamicin and vancomycin due to over-exposure of the pathogen to these antibiotics. This fact combined with the ongoing threat demands the identification of new therapeutic targets to combat E. faecium infections.In this present study, comparative proteome analysis, subtractive genomic approach, metabolic pathway analysis and additional drug prioritizing parameters were used to propose a potential novel drug targets for E. faecium strain DO. Comparative genomic analysis of Kyoto Encyclopedia of Genes and Genomes annotated metabolic pathways identified a total of 207 putative target proteins in E. faecium DO that showed no similarity to human proteins. Among them 105 proteins were identified as essential novel proteins that could serve as potential drug targets through further bioinformatic approaches; such as-prediction of subcellular localization, calculation of molecular weight, and web-based investigation of 3D structural characterization. Eventually 19 non-homologous essential proteins of E. faecium DO were prioritized and proved to have the eligibility to become novel broad-spectrum antibiotic targets. Among these targets aldehyde-alcohol dehydrogenase was found to be involved in maximum pathways, and therefore, was chosen as novel drug target. Interestingly, aldehyde-alcohol dehydrogenase enzyme contains two domains namely acetaldehyde dehydrogenase and alcohol dehydrogenase, on which a 3D structure homology modeling and in silico molecular docking were performed. Finally, eight molecules were confirmed as the most suitable ligands for aldehyde-alcohol dehydrogenase and hence proposed as the potential inhibitors of this target.In conclusion, being human non-homologous, aldehyde-alcohol dehydrogenase protein can be targeted for potential therapeutic drug development in future. However, laboratory based experimental research should be performed to validate our findings in vivo.

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.

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