No abstract

Novel therapeutic strategies are essential to address the current global antimicrobial resistance crisis.Branched molecules with multiple peripheral functionalities, known as dendrimers, have gained interest as antimicrobials and have varying levels of toxicity. Silver displays activity against several microorganisms only in its positively charged form. In this study, silver salts of generation 1 (G1) poly (propyl ether imine) (PETIM) dendron and dendrimers were synthesised and evaluated for their antimicrobial potential against sensitive and resistant bacteria. The purpose was to exploit the multiple peripheral functionalities of G1 PETIM dendron and dendrimers for the formation of silver salts containing multiple silver ions in a single molecule for enhanced antimicrobial activity at the lowest possible concentration.G1 PETIM dendron, dendrimers and their silver salts were synthesised and characterised by FT-IR, 1 H NMR and 13 C NMR. PETIM silver salts were evaluated against Hep G2, SKBR-3 and HT-29 cell lines for their cytotoxicity using the MTT assay. The G1 PETIM dendron/dendrimers, silver nitrate and silver salts of the G1 dendron (compound 13), G1 dendrimer with an aromatic core (compound 14) and an oxygen core (compound 15) were evaluated for activity against S. aureus and methicillin-resistant S. aureus (MRSA) by the broth dilution method. PETIM silver salts were found to be non-cytotoxic even up to 100 mg ml À1 . Minimum inhibitory concentration values of compounds 13, 14 and 15 against S. aureus were 52.1, 41.7 and 20.8 mg ml À1 while against MRSA they were 125.0, 26.0 and 62.5 mg ml À1 , respectively. The calculated fractional inhibitory concentration index further indicated that compound 14 specifically displayed additive effects against S. aureus and synergism against MRSA. The enhanced antimicrobial activities of the PETIM dendron/dendrimer-silver salts against both sensitive and resistant bacterial strains widen the pool of available pharmaceutical materials for optimizing treatment of bacterial infections.

We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains.