scholarly journals Subtractive genomics and molecular docking approach to identify drug targets against Stenotrophomonas maltophilia

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261111
Author(s):  
Hira Saleem ◽  
Usman Ali Ashfaq ◽  
Habibullah Nadeem ◽  
Muhammad Zubair ◽  
Muhammad Hussnain Siddique ◽  
...  
Keyword(s):  
Drug Targets ◽  
Stenotrophomonas Maltophilia ◽  
Acyl Carrier Protein ◽  
Multiple Drug Resistance ◽  
New Drugs ◽  
Multiple Drug ◽  
Carrier Protein ◽  
Homologous Proteins ◽  
Essential Proteins ◽  
Validation Experiment

Stenotrophomonas maltophilia is a multidrug resistant pathogen associated with high mortality and morbidity in patients having compromised immunity. The efflux systems of S. maltophilia include SmeABC and SmeDEF proteins, which assist in acquisition of multiple-drug-resistance. In this study, proteome based mapping was utilized to find out the potential drug targets for S. maltophilia strain k279a. Various tools of computational biology were applied to remove the human-specific homologous and pathogen-specific paralogous sequences from the bacterial proteome. The CD-HIT analysis selected 4315 proteins from total proteome count of 4365 proteins. Geptop identified 407 essential proteins, while the BlastP revealed approximately 85 non-homologous proteins in the human genome. Moreover, metabolic pathway and subcellular location analysis were performed for essential bacterial genes, to describe their role in various cellular processes. Only two essential proteins (Acyl-[acyl-carrier-protein]—UDP-N acetyl glucosamine O-acyltransferase and D-alanine-D-alanine ligase) as candidate for potent targets were found in proteome of the pathogen, in order to design new drugs. An online tool, Swiss model was employed to model the 3D structures of both target proteins. A library of 5000 phytochemicals was docked against those proteins through the molecular operating environment (MOE). That resulted in to eight inhibitors for both proteins i.e. enterodiol, aloin, ononin and rhinacanthinF for the Acyl-[acyl-carrier-protein]—UDP-N acetyl glucosamine O-acyltransferase, and rhazin, alkannin beta, aloesin and ancistrocladine for the D-alanine-D-alanine ligase. Finally the ADMET was done through ADMETsar. This study supported the development of natural as well as cost-effective drugs against S. maltophilia. These inhibitors displayed the effective binding interactions and safe drug profiles. However, further in vivo and in vitro validation experiment might be performed to check their drug effectiveness, biocompatibility and their role as effective inhibitors.

Proteome Mining for the Identification of Putative Drug Targets For Human Pathogen Clostridium Tetani

2019 ◽  
Vol 14 (6) ◽  
pp. 532-540 ◽  
Author(s):  
Anum Munir ◽  
Shaukat Iqbal Malik ◽  
Khalid Akhtar Malik
Keyword(s):  
Drug Targets ◽  
Cellular Localization ◽  
Pathogenic Bacteria ◽  
Homo Sapiens ◽  
Proteome Analysis ◽  
Essential Genes ◽  
Homologous Proteins ◽  
Clostridium Tetani ◽  
Essential Proteins ◽  
Localization Analysis

Background: Clostridium tetani are rod-like, anaerobic types of pathogenic bacteria of the genus Clostridium. It is Gram-positive in nature and appears as a tennis racket or drumsticks on staining with the dye. Tetanus is a neuromuscular disease wherein the Clostridium tetani exotoxin produces muscle fits in the host. Tetanus is the second leading cause of worldwide deaths occurring from the family of immunization-preventable diseases. Methods: In this research, subtractive proteome analysis of C. tetani was performed to identify putative drug targets. The proteins were subjected to blast analysis against Homo sapiens to exclude homologous proteins. The database of Essential Genes was used to determine the essential proteins of the pathogen. These basic proteins were additionally analyzed to anticipate the corresponding metabolic pathways. Results: Cellular localization analysis was carried out to determine the possibility of the protein presence in the outer membrane. The study has recognized 29 essential genes and 20 unique pathways of 2314 proteins as potential drug targets. There are 29 essential proteins, out of which, 3 membrane proteins were also identified as putative drug targets. Conclusion: Virtual screening in contrast to these proteins can be valuable in the identification of novel clinical compounds for the C. tetani infections in Homo sapiens.

scholarly journals Potential Drug Target Identification of Legionella pneumophila by Subtractive Genome Analysis: An In Silico Approach

2019 ◽  
Vol 35 (2) ◽  
pp. 102-107
Author(s):  
Md Sadikur Rahman Shuvo ◽  
Shahriar Kabir Shakil ◽  
Firoz Ahmed
Keyword(s):  
Legionella Pneumophila ◽  
Drug Targets ◽  
Pathogenic Bacteria ◽  
Genomic Analysis ◽  
Opportunistic Pathogen ◽  
Surface Proteins ◽  
Multi Drug Resistance ◽  
Therapeutic Drug ◽  
Homologous Proteins ◽  
Essential Proteins

Though Legionella pneumophila is an opportunistic pathogen, recent reports about multi drug resistance in L. pneumophila is alarming. Annotated whole genome provides a pool of information which is applied for therapeutic drug targets identification in pathogenic bacteria. Subtractive genomic analysis is a pragmatic approach to screen the essential proteins present in pathogen but absent in host. Phylogenetically closely related L. pneumophila str. Philadelphia and L. pneumophila str. ATCC43209 protein profiles were analyzed to identify putative drug targets. Paralogous duplicate profiles were primarily discarded using CD-hit suit. Six hundred and ninety one L. pneumophila str. Philadelphia and 690 L. pneumophila str. ATCC43209 human homologous proteins were excluded using blstP. Among the human non-homologous proteins, the essential proteins for bacteria were separated using DEG tool. For both strains, one hundred and nineteen essential proteins were marked which participate in various metabolic pathways. Among them 11 unique proteins were found. Beside it, 15 and 16 exposed surface proteins were present in strain Philadelphia and ATCC43209 respectively. These unique and cell surface proteins can be utilized for effective drug and vaccine targets. Bangladesh J Microbiol, Volume 35 Number 2 December 2018, pp 102-107

Subtractive Proteome Mining Approach Towards Unique Putative Drug Targets Identification for Salmonella Typhimurium

2019 ◽  
Vol 19 ◽  
Author(s):  
Rabia Iftikhar ◽  
Muhammad Rizwan ◽  
Sajid Khan ◽  
Azhar Mehmood ◽  
Anum Munir
Keyword(s):  
Salmonella Typhimurium ◽  
Drug Targets ◽  
Homo Sapiens ◽  
Essential Genes ◽  
Intestinal Lumen ◽  
Homologous Proteins ◽  
Essential Proteins ◽  
Contaminated Food ◽  
Potential Drug Targets ◽  
Infants And Young Children

: Salmonella typhimurium is rod-shaped bacteria with a Gram-negative genus, belonging to the Enterobacteriaceae family of microbes, invades the intestinal lumen of Human. Salmonella typhimurium is a root source, accounting for gastroenteritis in humans as well as in other mammals. Gastroenteritisis associated with Salmonella Typhimurium by interacting with the contaminated food and water, spread to nearby people in the area. Small intestines are attacked by Salmonella and then enter into the bloodstream momentarily, and are responsible for millions of mortalities and morbidities around the globe. Salmonella typhimurium toxins cause gastrointestiritis due to inflammation in the stomach and intestine in infants and young children. It accounts for millions of deaths with a higher incidence rate in developing countries. Methods: : In the current research, subtractive proteome mining has been done to recognize putative drug targets. The proteome was analyzed through blast in order to exclude homologous proteins. Bacterial essential proteins were predicted and the participation of the essential genes in the metabolic pathways has been analyzed. Results: : 36 essential genes and 15 unique pathways have been identified as potential drug targets among the total of 1934 proteins. The location of proteins is determined as an outer membrane. 3 proteins out of 36 essential proteins are recognized as putative drug targets. Conclusion:: In the future, virtual screening for the evaluation of novel clinical compounds for the identified proteins is effective and valuable for Salmonella Typhimurium infection in Homo sapiens.

Isolation, characterization, and genomic investigation of a phytopathogenic strain of Stenotrophomonas maltophilia

2021 ◽  
Author(s):  
Ming Hu ◽  
Chuhao Li ◽  
Yang Xue ◽  
Anqun Hu ◽  
Shanshan Chen ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Multiple Drug Resistance ◽  
Soft Rot ◽  
Fruit Rot ◽  
Extracellular Polysaccharides ◽  
Multiple Drug ◽  
Potential Contribution ◽  
White Stripe ◽  
Solid Media ◽  
Semi Solid

Stenotrophomonas maltophilia is ubiquitous in diverse environmental habitats. It alerts significant concern due to its increasing incidence of nosocomial and community-acquired infection in immunocompromised patients and multiple drug resistance. It is rarely reported as a phytopathogen except causing white stripe disease of rice in India and postharvest fruit rot of Lanzhou Lily. Recently, Dickeya zeae and S. maltophilia strains were simultaneously isolated from soft rot leaves of Clivia miniata in Guangzhou, China, and were both demonstrated pathogenic to the host. Compared with the D. zeae strains, S. maltophilia strains propagated faster for greater growth in LB medium and produced no cellulases or polygalacturonases, more proteases and fewer extracellular polysaccharides. Furthermore, S. maltophilia strains swam and swarmed dramatically less on semi-solid media, but formed extraordinarily more biofilms. Both D. zeae and S. maltophilia strains isolated from clivia caused rot symptoms on other monocot hosts, but not on dicots. Similar to previously reported S. maltophilia strains isolated from other sources, strain JZL8 survived under many antibiotic stresses. Complete genome sequence of S. maltophilia strain JZL8 consists of a chromosome of 4,635,432 bp without plasmid. Pan-genome analysis of JZL8 and 180 other S. maltophilia strains identified 50 JZL8-unique genes, seven of which implicates potential contribution of JZL8 pathogenicity on plants. JZL8 also contains 3 copies of T1SS, likely responsible for its greater production of proteases. Findings from this study extend our knowledge on the host range of S. maltophilia and provide insight into phenotypic and genetic features underlying the plant pathogenicity of JZL8.

scholarly journals A patient presenting with cholangitis due to Stenotrophomonas maltophilia and Pseudomonas aeruginosa successfully treated with intrabiliary colistine

2014 ◽  
Vol 6 (2) ◽  
Author(s):  
Pablo N. Pérez ◽  
María A. Ramírez ◽  
José A. Fernández ◽  
Laura Ladrón de Guevara
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Stenotrophomonas Maltophilia ◽  
Percutaneous Transhepatic Biliary Drainage ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
New Approach ◽  
Adequate Response ◽  
First Case ◽  
Transhepatic Biliary Drainage

Anatomical barriers for antibiotic penetration can pose a particular challenge in the clinical setting. <em>Stenotrophomonas maltophilia</em> (SM) and <em>Pseudomonas aeruginosa</em> (PA) are two pathogens capable of developing multiple drug-resistance (MDR) mechanisms. We report the case of a 56-year-old female patient with a permanent percutaneous transhepatic biliary drainage (PTBD), who was admitted to our hospital with a cholangitis due to a MDR <em>Escherichia coli</em> strain. Upon admission, culture-guided antimicrobial therapy was conducted and the biliary catheter was replaced, with poor clinical response. Subsequently, SM and PA were detected. Treatment with fosfomycin and colistine was initiated, again without adequate response. Systemic colistine and tigecycline along with an intrabiliary infusion of colistine for 5 days was then used, followed by parenteral fosfomycin and tigecycline for 7 days. The patient was then successfully discharged. This is the first case report we are aware of on the use of intrabiliary colistine. It describes a new approach to treating cholangitis by MDR bacteria in patients with a PTBD.

Refractory shock secondary to treatment with levofloxacin in an extremely low birth weight infant affected by Stenotrophomonas maltophilia pneumonia

2015 ◽  
Vol 4 (1) ◽  
Author(s):  
José Luis Leante-Castellanos ◽  
María Jesús Zamora-Gimeno ◽  
María José Gonzálvez-Candela ◽  
Amelia Chica-Marchal ◽  
Carmen Fuentes-Gutiérrez ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Stenotrophomonas Maltophilia ◽  
Late Onset ◽  
Multiple Drug Resistance ◽  
Extremely Low Birth Weight ◽  
Multiple Drug ◽  
Refractory Shock ◽  
Limited Experience ◽  
Drug Resistance Profile

Abstractis an important but rare cause of late onset neonatal sepsis in extremely low birth weight (ELBW) infants. These infections are difficult to treat due to the multiple drug resistance profile of the organism. One class of antibiotics available for use is the quinolones, such as ciprofloxacin and levofloxacin. However, the limited experience and known toxicity of levofloxacin raises further concerns regarding its use in this patient population. We present a case of refractory shock in an ELBW infant following the use of levofloxacin to treat

scholarly journals IN SILICO IDENTIFICATION OF NOVEL DRUG TARGETS IN ACINETOBACTER BAUMANNII BY SUBTRACTIVE GENOMIC APPROACH

2018 ◽  
Vol 11 (3) ◽  
pp. 230 ◽  
Author(s):  
Meenu Goyal ◽  
Citu Citu ◽  
Nidhi Singh
Keyword(s):  
Acinetobacter Baumannii ◽  
In Silico ◽  
Metabolic Pathways ◽  
Drug Targets ◽  
Potential Drug ◽  
Homologous Proteins ◽  
Essential Proteins ◽  
Novel Drug ◽  
Potential Drug Targets ◽  
Novel Drug Targets

 Objective: Multiple drug resistance (MDR) in bacteria, particularly Gram-negative bacilli, has significantly hindered the treatment of infections caused by these bacteria. This results in the need for identifying new drugs and drug targets for these bacteria. The objective of this study was to identify novel drug targets in Acinetobacter baumannii which has emerged as a medically important pathogen due to an increasing number of infections caused by it and its MDR property.Methods: In our study, we implemented in silico subtractive genomics approach to identify novel drug targets in A. baumannii American type culture collection 17978. Various databases and online software were used to build a systematic workflow involving comparative genomics, metabolic pathways analysis, and drug target prioritization to identify pathogen-specific novel drug targets.Results: First, 458 essential proteins were retrieved from a database of essential genes, and by performing BLASTp against Homo sapiens, 246 human non-homologous essential proteins were selected of 458 proteins. Metabolic pathway analysis performed by Kyoto Encyclopedia of Genes and Genomes–Kyoto Automatic Annotation Server revealed that these 246 essential non-homologous proteins were involved in 66 metabolic pathways. Among these metabolic pathways, 12 pathways were found to be unique to Acinetobacter that involved 37 non-homologous essential proteins. Of these essential non-homologous proteins, 19 proteins were found in common as well as unique metabolic pathways and only 18 proteins were unique to Acinetobacter. Finally, these target proteins were filtered to 9 potential targets, based on subcellular localization and assessment of druggability using Drug bank, ChEMBL, and literature.Conclusion: Our study identified nine potential drug targets which are novel targets in A. baumannii and can be used for designing drugs against these proteins. These drugs will be pathogen specific with no side effects on human host, as the potential drug targets are human non-homologous.

scholarly journals Divergent Acyl Carrier Protein Mediates Mitochondrial Fe-S Cluster Biosynthesis in Malaria Parasites

2021 ◽  
Author(s):  
Seyi Falekun ◽  
Jaime Sepulveda ◽  
Yasaman Jami-Alahmadi ◽  
Hahnbeom Park ◽  
James Wohlschlegel ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
Drug Targets ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Acid Synthesis ◽  
Complex Iii ◽  
Carrier Protein ◽  
Malaria Parasites ◽  
Cluster Biosynthesis

Plasmodium falciparum malaria parasites are early-diverging eukaryotes with many unusual metabolic adaptations. Understanding these adaptations will give insight into parasite evolution and unveil new parasite-specific drug targets. In contrast to human cells, the Plasmodium mitochondrion lacks type II fatty acid biosynthesis (FASII) enzymes yet curiously retains a divergent acyl carrier protein (mACP) incapable of modification by a 4-phosphopantetheine (Ppant) group required for canonical ACP function as the scaffold for fatty acid synthesis. We report that ligand-dependent knockdown of mACP expression is lethal to parasites, indicating an essential FASII-independent function. Decyl-ubiquinone rescues parasites temporarily from this lethal phenotype, suggesting a dominant dysfunction of the mitochondrial electron transport chain (ETC) followed by broader defects beyond the ETC. Biochemical studies reveal that Plasmodium mACP binds and stabilizes the Isd11-Nfs1 cysteine desulfurase complex required for Fe-S cluster biosynthesis, and mACP knockdown causes loss of both Nfs1 and the Rieske Fe-S cluster protein in ETC Complex III. This work identifies Ppant-independent mACP as an essential mitochondrial adaptation in Plasmodium malaria parasites that appears to be a shared metabolic feature of Apicomplexan pathogens, including Toxoplasma and Babesia. This parasite-specific adaptation highlights the ancient, fundamental role of ACP in mitochondrial Fe-S cluster biogenesis and reveals an evolutionary driving force to retain this interaction with ACP independent of its eponymous function in fatty acid synthesis.

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