Interplay between Supramolecular and Coordination Interactions in Synthetic Amphiphiles: Triggering Metal Starvation...

The present work highlights the implications of supramolecular interaction and metal coordination on the self-assembly behavior and bactericidal potential of salicaldehyde-(C1) and napthaldehyde-based (C2) amphiphiles against methicillin-resistant Staphylococcus aureus (MRSA). LB trough and atomic force microscope (AFM) analysis indicated the propensity of the amphiphiles to form a monolayer as well as spherical aggregates, with the critical micelle concentration (CMC) for C2 (7.0 μM) being lower than C1 (18.5 μM) in water. Formation of an amphiphile-metal complex was evidenced by ESI-MS, FTIR, FETEM-EDX, and ITC analysis. Growth of S. aureus MRSA 100 cells was remarkably impaired in the presence of 5.0 μM C1 or 20 μM C2 as compared to free cells or cells grown in the presence of equivalent levels of amphiphile-metal complexes, suggesting that the amphiphiles perhaps sequester metal and induce metal starvation in MRSA. C1 and C2 rendered superior membrane damage in MRSA and were less toxic to human embryonic kidney (HEK 293) cells as compared to their metal complexes. C1 and C2 rendered a dose-dependent inhibition of S. aureus biofilm formation, while revival of biofilm upon Zn(II) addition suggested that zinc starvation rendered by the amphiphiles may induce biofilm inhibition. C1 imposed a concentration-dependent metal starvation response in MRSA as there was an upregulation of the cntL gene and downregulation of cntA gene, which are involved in synthesis of the zincophore staphylopine (Stp) and transport of the Stp-Zn complex, respectively. ITC analysis revealed that binding of C1 and C2 to staphylococcal lipoteichoic acid (LTA) was stronger than the corresponding Zn(II) complexes, which perhaps accounted for the higher bactericidal potency of the amphiphiles. The study provides a fundamental understanding on how the chemistry-driven multimodal interaction of the amphiphile translates into growth inhibition and metal starvation in MRSA and advances the idea of combating drug resistance in pathogenic bacteria through amphiphiles, which are pluri-active.