Identification of novel non-homologous drug targets against Acinetobacter baumannii using subtractive genomics and comparative metabolic pathway analysis

Kaur, Harpreet; Kalia, Manmohit; Taneja, Neelam

doi:10.1016/j.micpath.2020.104608

Cited by 28 publications

(16 citation statements)

References 38 publications

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“…Bacterial RBPs, contrary to eukaryotic ones, can normally bind a wider number of sequences. For example, Hfq has a wide substrate selection, underling the different roles covered by this protein: from RNA chaperone to ribosome biogenesis, DNA compaction, protein–protein interactions, and involvement in RNA degradation machinery [ 8 , 34 , 35 ]. We characterized the crystal structure of rAB-Elavl, which retraces the common structure of the classical RRM domain: β1-α1-β2-β3-α2-β4, in which RNP1 and RNP2 are in the internal strands of the beta-sheet (β1-β3) [ 1 , 4 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of an RRM-Containing, RNA Binding Protein in Acinetobacter baumannii

et al. 2022

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Acinetobacter baumannii is a Gram-negative pathogen, known to acquire resistance to antibiotics used in the clinic. The RNA-binding proteome of this bacterium is poorly characterized, in particular for what concerns the proteins containing RNA Recognition Motif (RRM). Here, we browsed the A. baumannii proteome for homologous proteins to the human HuR(ELAVL1), an RNA binding protein containing three RRMs. We identified a unique locus that we called AB-Elavl, coding for a protein with a single RRM with an average of 34% identity to the first HuR RRM. We also widen the research to the genomes of all the bacteria, finding 227 entries in 12 bacterial phyla. Notably we observed a partial evolutionary divergence between the RNP1 and RNP2 conserved regions present in the prokaryotes in comparison to the metazoan consensus sequence. We checked the expression at the transcript and protein level, cloned the gene and expressed the recombinant protein. The X-Ray and NMR structural characterization of the recombinant AB-Elavl revealed that the protein maintained the typical β1α1β2β3α2β4 and three-dimensional organization of eukaryotic RRMs. The biochemical analyses showed that, although the RNP1 and RNP2 show differences, it can bind to AU-rich regions like the human HuR, but with less specificity and lower affinity. Therefore, we identified an RRM-containing RNA-binding protein actually expressed in A. baumannii.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of an RRM-Containing, RNA Binding Protein in Acinetobacter baumannii

et al. 2022

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“…For the survival of bacteria, essential genes are necessary [ 31 ]. Essential genes are preferred targets for vaccine development and antibacterial drugs [ 32 ]. Thus 407 essential genes were screened from non-redundant proteins.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Furthermore, the selected genes were subjected to BLASTp against the Virulence Factor Database by setting E-value cut-off to 10 −5 for determining the proteins possessing the highest virulence factor [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

“…For further structure-based studies, only those proteins that possess high antibiotic resistance were required. The BLASTp analysis was performed for essential virulent proteins against ARG-ANNOT by setting E-value cut-off to 10 −5 [ 24 ]. The resultant data set was of homologous essential proteins possessing high antibiotic resistance and was opted for further structure-based studies.…”

Section: Methodsmentioning

confidence: 99%

Subtractive genomics profiling for potential drug targets identification against Moraxella catarrhalis

et al. 2022

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Moraxella catarrhalis (M. catarrhalis) is a gram-negative bacterium, responsible for major respiratory tract and middle ear infection in infants and adults. The recent emergence of the antibiotic resistance M. catarrhalis demands the prioritization of an effective drug target as a top priority. Fortunately, the failure of new drugs and host toxicity associated with traditional drug development approaches can be avoided by using an in silico subtractive genomics approach. In the current study, the advanced in silico genome subtraction approach was applied to identify potential and pathogen-specific drug targets against M. catarrhalis. We applied a series of subtraction methods from the whole genome of pathogen based on certain steps i.e. paralogous protein that have extensive homology with humans, essential, drug like, non-virulent, and resistant proteins. Only 38 potent drug targets were identified in this study. Eventually, one protein was identified as a potential new drug target and forwarded to the structure-based studies i.e. histidine kinase (UniProt ID: D5VAF6). Furthermore, virtual screening of 2000 compounds from the ZINC database was performed against the histidine kinase that resulted in the shortlisting of three compounds as the potential therapeutic candidates based on their binding energies and the properties exhibited using ADMET analysis. The identified protein gives a platform for the discovery of a lead drug candidate that may inhibit it and may help to eradicate the otitis media caused by drug-resistant M. catarrhalis. Nevertheless, the current study helped in creating a pipeline for drug target identification that may assist wet-lab research in the future.

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Identification of novel non-homologous drug targets against Acinetobacter baumannii using subtractive genomics and comparative metabolic pathway analysis

Cited by 28 publications

References 38 publications

Identification and Characterization of an RRM-Containing, RNA Binding Protein in Acinetobacter baumannii

Identification and Characterization of an RRM-Containing, RNA Binding Protein in Acinetobacter baumannii

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

Subtractive genomics profiling for potential drug targets identification against Moraxella catarrhalis

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