Broadening Activity of Polymyxin by Quaternary Ammonium Grafting

Abstract

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.

Polymyxin B1 within the E. coli cell envelope: insights from molecular dynamics simulations

“…1. Interaction with LPS sugar residues (Berglund et al 2015;Jefferies et al 2017;Fu et al 2020;Ongwae et al 2020;Feigman et al 2018;Santos et al 2017;Jiang et al 2021a) 2. Polymyxin binding to lipid A headgroups (Berglund et al 2015;Jefferies et al 2017;Fu et al 2020;Ongwae et al 2020;Feigman et al 2018;Santos et al 2017;Jiang et al 2021a;Li et al 1862;Jiang et al 2020a;Li et al 2020;Jiang et al 2021b) 3.…”

“…Interaction with LPS sugar residues (Berglund et al 2015;Jefferies et al 2017;Fu et al 2020;Ongwae et al 2020;Feigman et al 2018;Santos et al 2017;Jiang et al 2021a) 2. Polymyxin binding to lipid A headgroups (Berglund et al 2015;Jefferies et al 2017;Fu et al 2020;Ongwae et al 2020;Feigman et al 2018;Santos et al 2017;Jiang et al 2021a;Li et al 1862;Jiang et al 2020a;Li et al 2020;Jiang et al 2021b) 3. Polymyxin insertion (insertion of polymyxin hydrophobic moieties into hydrophobic membrane core) (Berglund et al 2015;Jefferies et al 2017;Fu et al 2020;Ongwae et al 2020;Li et al 1862;Jiang et al 2020a;Li et al 2020;Jiang et al 2021b) 4.…”

“…Polymyxin binding to lipid A headgroups (Berglund et al 2015;Jefferies et al 2017;Fu et al 2020;Ongwae et al 2020;Feigman et al 2018;Santos et al 2017;Jiang et al 2021a;Li et al 1862;Jiang et al 2020a;Li et al 2020;Jiang et al 2021b) 3. Polymyxin insertion (insertion of polymyxin hydrophobic moieties into hydrophobic membrane core) (Berglund et al 2015;Jefferies et al 2017;Fu et al 2020;Ongwae et al 2020;Li et al 1862;Jiang et al 2020a;Li et al 2020;Jiang et al 2021b) 4. Polymyxin translocation (movement of the full polymyxin molecules into and through the hydrophobic membrane core) (Jefferies et al 2017;Jiang et al 2020a;Jiang et al 2021b).…”

“…Data from molecular simulations supports the initial stages of the proposed ‘self-promoted uptake’ mechanism while providing additional details on subsequent stages. Based on this, the movement of polymyxins through the outer membrane of polymyxin-susceptible bacterial strains may involve the following stages: Interaction with LPS sugar residues(Berglund et al 2015 ; Jefferies et al 2017 ; Fu et al 2020 ; Ongwae et al 2020 ; Feigman et al 2018 ; Santos et al 2017 ; Jiang et al 2021a ) Polymyxin binding to lipid A headgroups(Berglund et al 2015 ; Jefferies et al 2017 ; Fu et al 2020 ; Ongwae et al 2020 ; Feigman et al 2018 ; Santos et al 2017 ; Jiang et al 2021a ; Li et al 1862 ; Jiang et al 2020a ; b ; Li et al 2020 ; Jiang et al 2021b ) Polymyxin insertion (insertion of polymyxin hydrophobic moieties into hydrophobic membrane core)(Berglund et al 2015 ; Jefferies et al 2017 ; Fu et al 2020 ; Ongwae et al 2020 ; Li et al 1862 ; Jiang et al 2020a ; b ; Li et al 2020 ; Jiang et al 2021b ) Polymyxin translocation (movement of the full polymyxin molecules into and through the hydrophobic membrane core)(Jefferies et al 2017 ; Jiang et al 2020a ; b ; Jiang et al 2021b ). …”

Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming

“…In sharp contrast, at low concentrations where only monomers were present, these same molecules exhibited only antibacterial activity. Whether hybrid antimicrobial agents that are starting to emerge, (e.g., where quaternary ammonium groups are incorporated into potent antibiotics such as Polymyxin B and Vancomycin to aid in the destruction of bacterial membranes), could also take advantage of monomer control and taming is an intriguing question that, in my opinion, also warrants consideration [ 42 , 43 ].…”