Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies

Skariyachan, Sinosh; Ravishankar, Roshini; Gopal, Dharshini; Muddebihalkar, Aditi G.; Uttarkar, Akshay; Praveen, Prinith Kaveramma Uluvangada; Niranjan, Vidya

doi:10.1016/j.meegid.2020.104448

Cited by 18 publications

(7 citation statements)

References 43 publications

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“…In previous studies, MDS for longer durations were shown to be crucial in gaining better insight into the interaction profile. MDS has also been shown to provide better insight into drug interactions [ 32 , 33 , 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium Time-Series Genome Analysis Identifies AAC2′ as a Potential Drug Target with Naloxone Showing Potential Bait Drug Synergism

Niranjan¹,

Uttarkar²,

Murali³

et al. 2022

Molecules

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The World Health Organization has put drug resistance in tuberculosis on its list of significant threats, with a critical emphasis on resolving the genetic differences in Mycobacterium tuberculosis. This provides an opportunity for a better understanding of the evolutionary progression leading to anti-microbial resistance. Anti-microbial resistance has a great impact on the economic stability of the global healthcare sector. We performed a timeline genomic analysis from 2003 to 2021 of 578 mycobacterium genomes to understand the pattern underlying genomic variations. Potential drug targets based on functional annotation was subjected to pharmacophore-based screening of FDA-approved phyto-actives. Reaction search, MD simulations, and metadynamics studies were performed. A total of 4,76,063 mutations with a transition/transversion ratio of 0.448 was observed. The top 10 proteins with the least number of mutations were high-confidence drug targets. Aminoglycoside 2’-N-acetyltransferase protein (AAC2’), conferring resistance to aminoglycosides, was shortlisted as a potential drug target based on its function and role in bait drug synergism. Gentamicin-AAC2’ binding pose was used as a pharmacophore template to screen 10,570 phyto-actives. A total of 66 potential hits were docked to obtain naloxone as a lead — active with a docking score of -6.317. Naloxone is an FDA-approved drug that rapidly reverses opioid overdose. This is a classic case of a repurposed phyto-active. Naloxone consists of an amine group, but the addition of the acetyl group is unfavorable, with a reaction energy of 612.248 kcal/mol. With gentamicin as a positive control, molecular dynamic simulation studies were performed for 200 ns to check the stability of binding. Metadynamics-based studies were carried out to compare unbinding energy with gentamicin. The unbinding energies were found to be −68 and −74 kcal/mol for naloxone and gentamycin, respectively. This study identifies naloxone as a potential drug candidate for a bait drug synergistic approach against Mycobacterium tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Mycobacterium Time-Series Genome Analysis Identifies AAC2′ as a Potential Drug Target with Naloxone Showing Potential Bait Drug Synergism

Niranjan¹,

Uttarkar²,

Murali³

et al. 2022

Molecules

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“…affected better binding capacities with response regulator GacA (binding free energy = À7.2 kcal/mol) relative to attachment of meropenem and its target (binding free energy = À6.2 kcal/mol) in docking studies. GacA-celastrol complex confirmed conformational stability throughout the MD simulation process (Skariyachan et al, 2020). In a random trial conducted on 28 plants from south India possessing therapeutic activity when tested for their potential against mycotoxins produced by six fungi, aqueous extract of C. paniculatus seeds was found to significantly inhibit Trichophyton rubrum (Vonshak et al, 2003).…”

Section: Antimicrobial Activitymentioning

confidence: 86%

An extensive review on phytochemistry and pharmacological activities of Indian medicinal plantCelastrus paniculatusWilld

Nagpal

Garg

Arora

et al. 2022

Phytotherapy Research

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Celastrus paniculatus is a traditional herb belonging to the family Celastraceae and is widely used for a number of medicinal activities in the Indian Unani and Ayurvedic systems. In this study, the extensive literature search was carried out on phytochemistry, ethnobotanical uses and pharmacological activities of C. paniculatus (Willd.) in various scientific databases as well as patents. Research on phytochemical investigation has shown the presence of monoterpenes (linalool, α‐terpinyl acetate, nerol acetate), sesqueterpene esters (such as malkanguniol, malkangunin, valerenal, globulol, viridiflorol, cubenol and agarofuran derivatives), diterpenoids (such as phytone, isophytol), triterpenoids (such as lupeol, pristimerin, paniculatadiol, zeylasteral, zeylasterone, β‐amyrin, squalene), alkaloids (celapanin, celapanigin, celapagin, paniculatine, celastrine, maymyrsine), fatty acids, steroids (β‐sitosterol, carpesterol benzoate), flavonoids (paniculatin), benzoic acid, and vitamin C in this plant. All the reported pharmacological activities of this plant could be due to the presence of these phytochemicals. This plant possesses strong antioxidant activity which includes total flavonoid content, total phenolic content, nitric oxide scavenging activity and free radical scavenging activity. This plant possesses multiple pharmacological activities including cognition‐enhancing, neuroprotective, antipsychotic, anti‐depressant, antibacterial, anti‐arthritic, anti‐malarial, analgesic, anti‐inflammatory, anti‐fertility, cardiovascular, locomotor, anxiolytic, wound healing activity, anti‐spasmodic, hypolipidemic, anti‐cancerous and iron‐chelating activity with different extracts of this plant as well as various phytoconstituents present in this plant. The objective of this review article is to discuss in detail the reported ethnopharmacological uses, phytochemistry and various pharmacological activities of C. paniculatus.

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“…The different polysaccharides and pili are regulated by the GacA-GacS two-component system. GacA is involved in the positive regulation of the biofilm formation and production of virulence factors such as pyocyanin and lipase ( Skariyachan et al, 2020 ). Gene expression studies demonstrated that sub-MIC concentrations of MAF significantly downregulated the gac A gene, which plays a pivotal role in biofilm formation of P. aeruginosa .…”

Section: Discussionmentioning

confidence: 99%

Mitigation of quorum sensing mediated virulence factors of Pseudomonas aeruginosa: the role of Meldrum’s acid activated furan

Sadik,

Viswaswar,

Rajamoney

et al. 2024

Front. Microbiol.

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The rapid emergence of drug resistant pathogens is a major threat which has warranted the development of alternative strategies to combat infectious diseases. In this work, we have tested the anti-virulent activity of Meldrum’s acid activated furan (MAF) and 1,3-dimethyl barbituric acid activated furan (BAF) against Chromobacterium violaceum and Pseudomonas aeruginosa. It was found that MAF significantly reduced the violacein production and biofilm formation of C. violaceum at sub-inhibitory concentrations. The quorum sensing (QS) regulated virulence factors of P. aeruginosa including biofilm formation, motility, pigment production, and elastase activity were also found to be reduced considerably at sub-inhibitory concentrations of MAF. Additionally, MAF downregulated the expression of genes in the QS circuitry of P. aeruginosa, demonstrating the potential of MAF in lowering the pathogenicity of P. aeruginosa. In silico studies demonstrated the potential of MAF to compete with the signaling molecules of C. violaceum and P. aeruginosa for the QS receptor interaction. In vivo studies using Caenorhabditis elegans demonstrated the anti-pathogenicity of MAF by enhancing the survival of P. aeruginosa-infected C. elegans. These results suggest that activated furan compounds could be potential inhibitors of QS-mediated virulence factors in C. violaceum and P. aeruginosa, encouraging their use in combating multidrug-resistant pathogens.

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Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies

Cited by 18 publications

References 43 publications

Mycobacterium Time-Series Genome Analysis Identifies AAC2′ as a Potential Drug Target with Naloxone Showing Potential Bait Drug Synergism

Mycobacterium Time-Series Genome Analysis Identifies AAC2′ as a Potential Drug Target with Naloxone Showing Potential Bait Drug Synergism

An extensive review on phytochemistry and pharmacological activities of Indian medicinal plantCelastrus paniculatusWilld

Mitigation of quorum sensing mediated virulence factors of Pseudomonas aeruginosa: the role of Meldrum’s acid activated furan

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