Cheminformatics Validation of Plazomicin and Bioprospection of Putative Modulators of Aminoglycoside Modifying Enzymes from Gnaphalium affine towards Interventive Antibacterial Therapy

Abstract

Background: The relevance of aminoglycosides has decreased in recent times due to the prevalence of their modifying enzymes, such as aminoglycoside N-acetyltransferases (AAC) [e.g., AAC (6)-ly], aminoglycoside O-nucleotidyltransferases (ANT) [e.g., ANT (2”)] and aminoglycoside O-phosphotransferases (APH) [e.g., APH (3)-IIa)], which inactivate them. However, the recent development of plazomicin, which resists the modifying actions of some subclasses of AAC, ANT, and APH, has sparked renewed interest in aminoglycosides. This study aims to identify computationally potent and less toxic modulators of AAC (6)-ly, ANT (2”), and APH (3)-IIa from Gnaphalium affine (G. affine) that could be used in combinatory therapy with aminoglycosides. Methods: Potent and less toxic modulators of the three enzymes were identified using molecular docking, quantitative structure-activity relationship (QSAR) study, pharmacokinetics properties, and a 100 ns molecular dynamic simulation for stability and energy refinement. Results: The results show that plazomicin is a potent aminoglycoside-like antibiotic (probability of being active (Pa): 0.803) with significant binding free energies of –51.01, –53.01, and –81.86 kcal/mol against ANT (2”), APH (3)-IIa, and AAC (6)-ly, respectively. The high binding free energy of plazomicin against the three enzymes correlated with its predicted high bioactivity against them. Interestingly, bioprospecting the metabolites of G. affine against the three enzymes revealed that the top-ranked compounds in each case formed thermodynamically stable complexes (root mean square deviation (RMSD): 1.43–2.37 Å) with pharmacokinetic properties that potentiated them as less toxic enzyme inhibitors than plazomicin. Conclusions: Overall, the thermodynamic binding free energy and the QSAR analyses identified alpha-cedrol as a putative inhibitor of the three enzymes. The binding free energy of alpha-cedrol ranged from –46.26 to –53.27 kcal/mol, which is comparable to that of plazomicin against ANT (2”) and APH (3)-IIa. Further validation of alpha-cedrol as a novel inhibitor of the investigated enzymes is highly recommended. Both in vitro and in vivo studies should be conducted to confirm this efficacy.