Abstract
K11 is a synthetic peptide originating from the introduction of a lysine residue in position 11 within the sequence of a rationally designed antibacterial scaffold. Despite its remarkable antibacterial properties towards many ESKAPE bacteria and its optimal therapeutic index (320), a detailed description of its mechanism of action is missing. As most antimicrobial peptides act by destabilizing the membranes of the target organisms, we investigated the interaction of K11 with biomimetic membranes of various phospholipid compositions by liquid and solid-state NMR. Our data show that K11 can selectively destabilize bacterial biomimetic membranes and torque the surface of their bilayers. The same is observed for membranes containing other negatively charged phospholipids which might suggest additional biological activities. Molecular dynamic simulations reveal that K11 can penetrate the membrane in four steps: after binding to phosphate groups by means of the lysine residue at the N-terminus (anchoring), three couples of lysine residues act subsequently to exert a torque in the membrane (twisting) which allows the insertion of aromatic side chains at both termini (insertion) eventually leading to the flip of the amphipathic helix inside the bilayer core (helix flip and internalization).
Highlights
IntroductionIn the quest for new molecules able to overcome this major health issue, antimicrobial peptides (AMPs) are promising alternatives to classical antibiotics, due to their low tendency to resistance [6]
The persistent use of antibiotics, self-medication and exposure to nosocomial infections has provoked the emergence of multidrug resistant (MDR) bacteria worldwide [1–4].The term “ESKAPE” was adopted to refer to some of the most relevant pathogens associated with the highest risk of mortality by the World Health Organization (WHO) [5], namelyEnterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.In the quest for new molecules able to overcome this major health issue, antimicrobial peptides (AMPs) are promising alternatives to classical antibiotics, due to their low tendency to resistance [6]
Several AMPs have been rationally optimized and in this work we focus on K11, a synthetic AMP which was reported to exert antimicrobial action against many of the mentioned ESKAPE bacteria such as Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Klebsiella pneumoniae [14,15]
Summary
In the quest for new molecules able to overcome this major health issue, antimicrobial peptides (AMPs) are promising alternatives to classical antibiotics, due to their low tendency to resistance [6]. AMPs are natural peptides found in all life kingdoms which can be considered components of the innate immunity against bacteria and fungi, parasites, virus and cancer. Their reduced tendency to resistance is intrinsically due to their mechanism of action causing the selective disruption of bacterial membranes by acting on the lipidic organization of membranes whose lipid composition cannot be changed by a simple point mutation. While exceptions exist [7], their efficacy is proven by the fact that they have been evolutionarily optimized over millions of years, their fast killing rate discourages the rise of drug-resistant mutants [8] and horizontal transfer of resistance genes against
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