Protonation State-dependent Interaction of Polycationic Polymyxins with the Pseudomonas aeruginosa Outer Membrane Using Colistin A as a Model

The rapid spread of antimicrobial
resistance (AMR) has relaunched
Colistin A, a member of the polycationic polymyxin (PMBs) family,
as a last resort option against infection by Gram-negative pathogens
such as Pseudomonas aeruginosa. However,
the presence of positively charged α,γ-Diamino Butyric
acid (Dab) moieties in PMBs is associated with clinical toxicity,
so efforts have been made toward the development of derivatives with
a reduced total charge. In this study, we used all-atom molecular
dynamics (MD) simulations to elucidate the interaction of PMBs with
an evolved model of the P. aeruginosa outer membrane (OM) that includes Lipid A and the entire oligosaccharide
core. To investigate the potential effects of pH and total charge
on OM perturbation by Colistin A, used as a model scaffold, four different
protonation states were studied. Results reveal that the Colistin
A equipped with an overall +2 formal charge deeply penetrates the
OM, displaces Ca2+ ions within the simulated time scale,
and destabilizes OM integrity with a higher efficacy than other protonation
states. These results highlight the importance of the total charge
of small molecules directed toward the OM of Gram-negative pathogens
such as P. aeruginosa, providing additional
insights into the mechanism of action of Colistin A, essential for
guiding the rational design of effective PMB derivatives.