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

Abstract

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.

Integrated Pangenome Analysis and Pharmacophore Modeling Revealed Potential Novel Inhibitors against Enterobacter xiangfangensis

“…The current study screened for potential novel putative therapeutic targets in E. xiangfangensis using a pan genome and subtractive genomics strategy. The potential therapeutic targets of several bacteria, including Stenotrophomonas maltophilia [ 53 ], Mycobacterium tuberculosis [ 54 ], and Streptococcus gallolyticus [ 55 ] have also been predicted using these methods. Although, some additional analyses have been performed in our study that make it innovative from other studies, such as prediction of molecular function and biological processes, transmembrane helices, and druggability analysis.…”

Computer-Based Identification of Potential Druggable Targets in Multidrug-Resistant Acinetobacter baumannii: A Combined In Silico, In Vitro and In Vivo Study

“…To the best of our knowledge, this is the first time that OGEE was used to retrieve essential proteins. Most previous similar studies have used databases such as the Database of Essential Genes (DEG) and Geptop instead [ 12 , 13 , 15 , 17 ]. Avoiding possible undesired effects in human hosts is important, so essential proteins that are non-homologous to the human proteome were identified.…”

“…These ligands were mostly experimental, where few were nutraceutical. Unlike most of the similar studies [ 16 , 17 ], the druggability channel was prioritized, as finding possible interacting ligands was a main aim of this study.…”

“…Using the subtractive proteomics approach, potential drug targets were previously identified in several other pathogens, including Escherichia coli , Helicobacter pylori , Mycobacterium avium , Pseudomonas aeruginosa , Shigella flexneri , Staphylococcus aureus , Staphylococcus saprophyticus , Stenotrophomonas maltophilia and Streptococcus pneumoniae [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Although potential drug targets in A. baumannii have been identified in former studies [ 20 , 21 , 22 ], the current study proceeds to further validate the data obtained by the in silico approach.…”