Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption

Abstract

With increasing rates of resistance toward commonly used antibiotics, especially among Gram-negative bacteria, there is renewed interested in polymyxins. Polymyxins are lipopeptide antibiotics with potent anti-Gram-negative activity and are generally believed to target lipid A, the lipopolysaccharide (LPS) anchor found in the outer membrane of Gram-negative bacteria. To characterize the stereochemical aspects of their mechanism(s) of action, we synthesized the full enantiomers of polymyxin B and the polymyxin B nonapeptide (PMBN). Both compounds were compared with the natural compounds in biological and biophysical assays, revealing strongly reduced antibacterial activity for the enantiomeric species. The enantiomeric compounds also exhibit reduced LPS binding, lower outer membrane (OM) permeabilization, and loss of synergetic potential. These findings provide new insights into the stereochemical requirements underlying the mechanisms of action of polymyxin B and PMBN.

Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity

“…33,35,36 Interestingly, while the potentiating effect of PMBN is severely diminished against polymyxin-resistant bacteria, full-length polymyxins do exhibit synergistic activity against such strains. 13,31 We were therefore interested in also assessing the capacity of our novel polymyxin 8d to potentiate the activity of Gram-positive specific antibiotics against polymyxin-resistant bacteria.…”

“…[8][9][10] Mechanistically, the polymyxins target lipid A, the central membrane-embedded anchor of bacterial lipopolysaccharide (LPS). [11][12][13] While the activity of many antibiotics is limited by poor permeability across the Gramnegative outer membrane (OM), this is not an issue for the polymyxins, as their target is found on the outer surface of the OM. Upon binding to LPS in the OM, polymyxins effectively destabilize the OM and in the process enhance their own uptake to the periplasmic space by so-called 'selfpromoted uptake'.…”

To Fold or Not to Fold: Diastereomeric Optimization of an α-Helical Antimicrobial Peptide

“…Membrane disruptive antimicrobial peptides (AMPs), which occur naturally as part of the innate immune system, offer an opportunity to address multidrug-resistant (MDR) bacteria because of their unspecific mechanism of action, against which resistance does not occur easily. − Such AMPs are however unstable in serum and most often toxic owing to their membrane disruptive amphiphilic and usually α-helical structure triggering their antibacterial effect. Their properties can be improved by sequence optimization, − whereby the most versatile approach consists in introducing non-natural structural elements such as d -amino acids, − non-natural residues, β- or γ-amino acids, , isopeptide bonds, or entirely non-peptidic elements such as spermine or fatty acids. , A complete redesign of AMPs is also possible in the form of dimers, cyclic or bicyclic staples, − small molecules, peptoids, , foldamers, or dendrimers. , …”

A Stepwise Targeting and Antibacterial Strategy by Leukocyte Membrane-Based Conjugated Oligomer Nanoparticles

“…19,22 Polymyxin B is a cationic antimicrobial agent that mainly acts on the cell walls of Gram-negative bacteria. 23,24 Polycationic peptide rings bind to lipid A of LPS and can target nanomaterials to bacterial surfaces. 19,25 Therefore, we designed a stepwise targeted biomimetic antibacterial material from the perspective of inflammation, which renders a new thought for the development of antibacterial materials in the future.…”

“…Although leukocyte membranes can help transport nanomaterials to the site of inflammation, the dense lipopolysaccharide (LPS) structure on the outer membrane of Gram-negative bacteria forms a natural barrier that hinders the entry of drugs, ROS, and other substances, making the treatment of Gram-negative bacterial infections more difficult. − Therefore, if it can be more accurately targeted to the surface of Gram-negative bacteria, the antibacterial effect of Gram-negative infection will be further improved. To further rapidly identify and locate the surface of Gram-negative bacteria, polymyxin B (PMB) was inserted into the cell membrane via liposomes. , Polymyxin B is a cationic antimicrobial agent that mainly acts on the cell walls of Gram-negative bacteria. , Polycationic peptide rings bind to lipid A of LPS and can target nanomaterials to bacterial surfaces. , Therefore, we designed a stepwise targeted biomimetic antibacterial material from the perspective of inflammation, which renders a new thought for the development of antibacterial materials in the future.…”