Computational Insights and In Vitro Validation of Antibacterial Potential of Shikimate Pathway-Derived Phenolic Acids as NorA Efflux Pump Inhibitors

Abstract

The expression of the efflux pump systems is the most important mechanism of antibiotic resistance in bacteria, as it contributes to reduced concentration and the subsequent inactivity of administered antibiotics. NorA is one of the most studied antibacterial targets used as a model for efflux-mediated resistance. The present study evaluated shikimate pathway-derived phenolic acids against NorA (PDB ID: 1PW4) as a druggable target in antibacterial therapy using in silico modelling and in vitro methods. Of the 22 compounds evaluated, sinapic acid (−9.0 kcal/mol) and p-coumaric acid (−6.3 kcal/mol) had the best and most prominent affinity for NorA relative to ciprofloxacin, a reference standard (−4.9 kcal/mol). A further probe into the structural stability and flexibility of the resulting NorA-phenolic acids complexes through molecular dynamic simulations over a 100 ns period revealed p-coumaric acid as the best inhibitor of NorA relative to the reference standard. In addition, both phenolic acids formed H-bonds with TYR 76, a crucial residue implicated in NorA efflux pump inhibition. Furthermore, the phenolic acids demonstrated favourable drug likeliness and conformed to Lipinski’s rule of five for ADME properties. For the in vitro evaluation, the phenolic acids had MIC values in the range 31.2 to 62.5 μg/mL against S. aureus, and E. coli, and there was an overall reduction in MIC following their combination with ciprofloxacin. Taken together, the findings from both the in silico and in vitro evaluations in this study have demonstrated high affinity of p-coumaric acid towards NorA and could be suggestive of its exploration as a novel NorA efflux pump inhibitor.

Molecular docking analysis and evaluation of the antimicrobial properties of the constituents of Geranium wallichianum D. Don ex Sweet from Kashmir Himalaya

“…Interestingly, elatine and kaempherol showed highest binding affinities as compared to already known natural inhibitors against PBP. The highest binding affinity of kaempherol was also supported by molecular simulation study on the interaction between tyrosinase and flavonoids from Sea Buckthorn 60 , 61 . Another well-known antimicrobial target is (DHPS) is an essential enzyme in the biosynthesis of dihydrofolate in microorganisms.…”

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

“…Molecular docking is an effective method aimed at determining the interaction and the mode of binding of compounds to the active site of the enzyme [19]. It depicts the competence of the ligand at the enzyme catalytic site [17], and a compound or ligand with the highest negative binding score is identified as having the best affinity for the enzyme [39]. This can be seen with vitexin, orientin, and apigenin revealing the most negative score (-7.3 kcal/mol) for PTP1B in this study which was at par with ursolic acid (-7.4 kcal/mol), the standard drug.…”

Pathfinder-Driven Chemical Space Exploration and Multiparameter Optimization in Tandem with Glide/IFD and QSAR-Based Active Learning Approach to Prioritize Design Ideas for FEP+ Calculations of SARS-CoV-2 PLpro Inhibitors

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