Differential analysis of Orientia tsutsugamushi genomes for therapeutic target identification and possible intervention through natural product inhibitor screening

Basharat, Zarrin; Akhtar, Umaimah; Khan, Kanwal; Alotaibi, Ghallab; Jalal, Khurshid; Abbas, Muhammad; Hayat, Ajmal; Ahmad, Diyar; Hassan, Syed Shah

doi:10.1016/j.compbiomed.2021.105165

Cited by 17 publications

(8 citation statements)

References 43 publications

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“…The pan-genome curve represented the B pan = 0.320 (i.e., <1) resulting in the open nature of the pathogen ( Figure 1 ). However, it is hypothesized that the pan-genome will continue to be accessible to new bacterial species as long as evolution and horizontal gene transfers are there [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Alturki

Mashraqi

Jalal

et al. 2022

Cancers

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Colorectal cancer (CRC) ranks third among all cancers in terms of prevalence. There is growing evidence that gut microbiota has a role in the development of colorectal cancer. Fusobacterium nucleatum is overrepresented in the gastrointestinal tract and tumor microenvironment of patients with CRC. This suggests the role of F. nucleatum as a potential risk factor in the development of CRC. Hence, we aimed to explore whole genomes of F. nucleatum strains related to CRC to predict potential therapeutic markers through a pan-genome integrated subtractive genomics approach. In the current study, we identified 538 proteins as essential for F. nucleatum survival, 209 non-homologous to a human host, and 12 as drug targets. Eventually, riboflavin synthase (RiS) was selected as a therapeutic target for further processing. Three different inhibitor libraries of lead-like natural products, i.e., cyanobactins (n = 237), streptomycins (n = 607), and marine bacterial secondary metabolites (n = 1226) were screened against it. After the structure-based study, three compounds, i.e., CMNPD3609 (−7.63) > Malyngamide V (−7.03) > ZINC06804365 (−7.01) were prioritized as potential inhibitors of F. nucleatum. Additionally, the stability and flexibility of these compounds bound to RiS were determined via a molecular dynamics simulation of 50 ns. Results revealed the stability of these compounds within the binding pocket, after 5 ns. ADMET profiling showed compounds as drug-like, non-permeable to the blood brain barrier, non-toxic, and HIA permeable. Pan-genomics mediated drug target identification and the virtual screening of inhibitors is the preliminary step towards inhibition of this pathogenic oncobacterium and we suggest mouse model experiments to validate our findings.

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Section: Resultsmentioning

confidence: 99%

“…[ 28 , 33 ]. Subtractive genome analysis is an effective method of finding the gene or group of genes responsible for a certain characteristic in an organism [ 34 ]. It helps discover the systemic variety in a given organism by analyzing its full genomic array.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Alturki

Mashraqi

Jalal

et al. 2022

Cancers

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“…Likewise, resistance protein identification was also performed. Resistance proteins are those which are responsible for the efflux of various antibiotic from the bacterial cell to counteract the drug action [71]. The subcellular localization of shortlisted proteins was also predicted for the identification of cytoplasmic protein for the drug targets and cell membrane protein for the construction of multi-epitope vaccine [72].…”

Section: Discussionmentioning

confidence: 99%

Immunoinformatic-guided designing of multi-epitope vaccine construct against Brucella Suis 1300

2022

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Brucella suis mediates the transmission of brucellosis in humans and animals and a significant facultative zoonotic pathogen found in livestock. It has the capacity to survive and multiply in a phagocytic environment and to acquire resistance under hostile conditions thus becoming a threat globally. Antibiotic resistance is posing a substantial public health threat, hence there is an unmet and urgent clinical need for immune-based non-antibiotic methods to treat brucellosis. Hence, we aimed to explore the whole proteome of Brucella suis to predict antigenic proteins as a vaccine target and designed a novel chimeric vaccine (multi-epitope vaccine) through subtractive genomics-based reverse vaccinology approaches. The applied subsequent hierarchical shortlisting resulted in the identification of Multidrug efflux Resistance-nodulation-division (RND) transporter outer membrane subunit (gene BepC) that may act as a potential vaccine target. T-cell and B-cell epitopes have been predicted from target proteins using a number of immunoinformatic methods. Six MHC I, ten MHC II, and four B-cell epitopes were used to create a 324-amino-acid MEV construct, which was coupled with appropriate linkers and adjuvant. To boost the immunological response to the vaccine, the vaccine was combined with the TLR4 agonist HBHA protein. The MEV structure predicted was found to be highly antigenic, non-toxic, non-allergenic, flexible, stable, and soluble. To confirm the interactions with the receptors, a molecular docking simulation of the MEV was done using the human TLR4 (toll-like receptor 4) and HLAs. The stability and binding of the MEV-docked complexes with TLR4 were assessed using molecular dynamics (MD) simulation. Finally, MEV was reverse translated, its cDNA structure was evaluated, and then, in silico cloning into an E. coli expression host was conducted to promote maximum vaccine protein production with appropriate post-translational modifications. These comprehensive computer calculations backed up the efficacy of the suggested MEV in protecting against B. suis infections. However, more experimental validations are needed to adequately assess the vaccine candidate's potential. Highlights• Subtractive genomic analysis and reverse vaccinology for the prioritization of novel vaccine target • Examination of chimeric vaccine in terms of allergenicity, antigenicity, MHC I, II binding efficacy, and structural-based studies • Molecular docking simulation method to rank based vaccine candidate and understand their binding modes

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“…Genome sequence availability is a boon for bioinformatics based studies, where algorithms and softwares can be used to mine therapeutic targets and explore druggable potential of a bacteria [ 9 ]. This approach has previously been implemented for identifying therapeutic targets in drug resistant Salmonella typhi [ 10 ], Enterobacteriacea family [ 11 ], Bacillus sp.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic target mapping from the genome of Kingella negevensis and biophysical inhibition assessment through PNP synthase binding with traditional medicinal compounds

et al. 2023

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Kingella negevensis belongs to the Neisseriaceae family. It is implied that it has significant virulence potential due to RTX toxin production, which can cause hemolysis. It usually colonizes the orophayrynx of pediatric population, along with Kingella kingae but has also been isolated from vagina. Todate no report on its drug targets is present, therefore putative therapeutic targets were identified from its genomic sequence data. Traditional Chinese ( n > 36,000) and Indian medicinal compounds ( n > 2000) were then screened against its pyridoxine 5'-phosphate synthase, a vital therapeutic target. Prioritized TCM compounds included ZINC02525131, ZINC33833737 and ZINC85486932, and Cadiyenol, 9,11,13-Octadecatrienoic acid and 6-Gingerol from Indian medicinal library. Molecular dynamics simulation of top compounds revealed ZINC02525131 as having best stability for 100 ns, compared to Cadiyenol. ADMET profiling was then done, along with physiologically based pharmacokinetic simulation of these compounds in a population of 200 individuals, for 12 h to see fate of the ingested compound. Additionally, the impact of these compounds in a population with cirrhosis and renal impairment was also simulated. We imply in light of all the studied parameters of safety and bioavailability, etc., that 6-Gingerol from Zingiber officinalis rhizome must be proceeded further for in vitro and in vivo testing for inhibition of K. negevensis. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-023-10604-y.

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Differential analysis of Orientia tsutsugamushi genomes for therapeutic target identification and possible intervention through natural product inhibitor screening

Cited by 17 publications

References 43 publications

Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Therapeutic Target Identification and Inhibitor Screening against Riboflavin Synthase of Colorectal Cancer Associated Fusobacterium nucleatum

Immunoinformatic-guided designing of multi-epitope vaccine construct against Brucella Suis 1300

Therapeutic target mapping from the genome of Kingella negevensis and biophysical inhibition assessment through PNP synthase binding with traditional medicinal compounds

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