45th Global Congress on Infectious Diseases: Research on Diagnosis and Therapeutics
Jamiu Olaseni Aribisala1, Talent Raymond Makhanya2, Saheed Sabiu1*
1Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, P.O. Box 1334, Durban 4000, South Africa.
2Department of Chemistry, Faculty of Applied Sciences, Durban University of Technology, P.O. Box 1334, Durban 4000, South Africa.
Citation: Aribisala JO, Makhanya TR, Sabiu S (2023) Cheminformatics Identification of Phenolics as Modulators of Penicillin Binding Protein (PBP) 2x of Streptococcus pneumoniae towards Interventive Antibacterial Therapy. SciTech Infectious Diseases 2023.
Received: August 28, 2023 Accepted: September 01, 2023 Published: September 01, 2023
Infections caused by multidrug-resistant Streptococcus pneumoniae remain the leading cause of pneumonia-related deaths in children < 5 years globally, and mutations in penicillin-binding protein (PBP) 2x have been identified as the major cause of resistance in the organisms to beta-lactams. Thus, the development of new modulators with enhanced binding of PBP2x is highly encouraged. In this study, phenolics, due to their reported antibacterial activities, were screened against the active site of PBP2x using structure-based pharmacophore and molecular docking techniques, and the ability of the top-hit phenolics to inhibit the active and allosteric sites of PBP2x was refined through 120 ns molecular dynamic simulation. Except for gallocatechin gallate (-14.93 kcal/mol) and lysidicichin (-33.53 kcal/mol), respectively, at the active and allosteric sites of PBP2x, the top-hit phenolics had higher negative binding free energy (ΔGbind) than amoxicillin [active site (-19.23 kcal/mol), allosteric site (-33.75 Kcal/mol). Compared to the apo-PBP2x, binding of the top-hits at the allosteric site generally caused higher fluctuations of Ser337 (the catalytic residue in PBP2x), suggesting the lesser involvement of the residue in intramolecular binding of adjacent residues. Although silicristin had the best broad-spectrum effects at the active (-38.41 kcal/mol) and allosteric sites (-50.54 kcal/mol) of PBP2x, the high thermodynamic entropy (4.90 Å) of the resulting complex might suggest the need for its possible structural refinement for enhanced potency. Interestingly, silicristin had a predicted synthetic feasibility score of < 5 and quantum calculations using the DFT B3LYP/6-31G+ (dp) revealed that silicristin is less stable and more reactive than amoxicillin. These findings point to the possible benefits of the top-hit phenolics, and most especially silicristin, in the direct and synergistic treatment of infections caused by S. pneumoniae. However, further confirmatory in vitro studies on the top hits are highly recommended, and work is ongoing in this regard.
Keywords: Penicillin binding protein, Phenolics, Molecular dynamic simulation, Antibacterial, Streptococcus pneumoniae
