Broadening Activity of Polymyxin by Quaternary Ammonium Grafting.
George M OngwaeKelly R MorrisonRyan A AllenSeonghoon KimWonpil ImWilliam M WuestMarcos M PiresPublished in: ACS infectious diseases (2020)
Bacterial pathogens continue to impose a tremendous health burden across the globe. Here, we describe a novel series of polymyxin-based agents grafted with membrane-active quaternary ammonium warheads to combine two important classes of Gram-negative antimicrobial scaffolds. The goal was to deliver a targeted quaternary ammonium warhead onto the surface of bacterial pathogens using the outer membrane homing properties of polymyxin. The most potent agents resulted in new scaffolds that retained the ability to target Gram-negative bacteria and had limited toxicity toward mammalian cells. We showed, using a molecular dynamics approach, that the new agents retained their ability to engage in specific interactions with lipopolysaccharide molecules. Significantly, the combination of quaternary ammonium and polymyxin widens the activity to the pathogen Staphylococcus aureus. Our results serve as an example of how two membrane-active agents can be combined to produce a class of novel scaffolds with potent biological activity.
Keyphrases
- gram negative
- multidrug resistant
- molecular dynamics
- staphylococcus aureus
- ionic liquid
- tissue engineering
- public health
- healthcare
- density functional theory
- inflammatory response
- toll like receptor
- oxidative stress
- escherichia coli
- anti inflammatory
- immune response
- lps induced
- climate change
- methicillin resistant staphylococcus aureus
- drug delivery