Inappropriate and uncontrolled use of antibiotics results in the emergence of antibiotic resistance, thereby threatening the present clinical regimens to treat infectious diseases. Therefore, new antimicrobial agents that can prevent bacteria from developing drug resistance are urgently needed. Selective disruption of bacterial membranes is the most effective strategy for combating microbial infections as accumulation of genetic mutations will not allow for the emergence of drug resistance against these antimicrobials. In this work, we tested cholic acid (CA) derived amphiphiles tethered with different alkyl chains for their ability to combat Gram-positive bacterial infections. In-depth biophysical and biomolecular simulation studies suggested that the amphiphile with a hexyl chain (6) executes more effective interactions with Gram-positive bacterial membranes as compared to other hydrophobic counterparts. Amphiphile 6 is effective against multidrug resistant Gram-positive bacterial strains as well and does not allow the adherence of S. aureus on amphiphile 6 coated catheters implanted in mice. Further, treatment of wound infections with amphiphile 6 clears the bacterial infections. Therefore, the current study presents strategic guidelines in design and development of CA-derived membrane-targeting antimicrobials for Gram-positive bacterial infections.
Keywords: MD simulations; antibacterial; antimicrobials; bile acids; membrane interactions.