Lipid II Binding and Transmembrane Properties of Various Antimicrobial Lanthipeptides

Abstract

There has been an alarming rise in antibacterial resistant infections in recent years due to the widespread use of antibiotics, and there is a dire need for the development of new antibiotics utilizing novel modes of action. Lantibiotics are promising candidates to engage in the fight against resistant strains of bacteria due to their unique modes of action, including interference with cell wall synthesis by binding to lipid II and creating pores in bacterial membranes. In this study, we use atomic-scale molecular dynamics computational studies to compare both the lipid II binding ability and the membrane interactions of five lanthipeptides that are commonly used in antimicrobial research: nisin, Mutacin 1140 (MU1140), gallidermin, NVB302, and NAI107. Among the five peptides investigated, nisin is found to be the most efficient at forming water channels through a membrane, whereas gallidermin and MU1140 are found to be better at binding the lipid II molecules. Nisin’s effectiveness in facilitating water transport across the membrane is due to the creation of several different water trajectories along with no significant water delay points along the paths. The shorter peptide deoxyactagardine B (NVB302) was found to not form a water channel. These detailed observations provide insights into the dual mechanisms of the action of lantibiotic peptides and can facilitate the design and development of novel lanthipeptides by strategic placement of different residues.

Purification, characterization, and mode of action of Sakacin ZFM225, a novel bacteriocin from Lactobacillus sakei ZFM225

“…Bacteriocins need a target molecule on the surface of sensitive cells to be active. It is now clear that the antibacterial mechanism of nisin is due to Lipid Ⅱ, which mediates the formation of cell membrane pores while preventing the formation of the cell wall of sensitive bacteria to reach antibacterial effects [ 30 ], so do Gallidermin and Mutacin 1140 [ 31 ]. According to the combined test, we have known that the specific target of Sakacin ZFM225 in the cell membrane wasn't Lipid Ⅱ, which promoted the development of an action mechanism at the molecular level.…”

The Synergistic Antimicrobial Effect and Mechanism of Nisin and Oxacillin against Methicillin-Resistant Staphylococcus aureus

“…NIS has an inhibitory effect on Gram-positive bacteria including S. aureus , it can form permeable pores in cell membrane of target cells, and it can also inhibit the synthesis of bacterial cell walls, resulting in damage of cell wall integrity and intracellular components leakage, causing bacterial death [ 12 ]. Oxacillin is the semisynthetic β-lactam antibiotics, however, penicillin-binding protein PBP2a of MRSA has significantly lower affinity for β-lactams, allows cell-wall biosynthesis, which is the target of β-lactams.…”

“…For antibacterial mechanism, NIS is similar to glycopeptide antibiotics, showing a strong affinity for lipid II (precursor of peptidoglycan synthesis); it binds to lipid II to form a complex, thereby hindering the normal synthesis of peptidoglycan, thus inhibiting the formation of bacterial cell walls [ 10 , 11 ]. NIS can also form transmembrane pores which dissipate proton-motive force and affect some energy-dependent reactions in cell, causing the release of cytoplasmic components and directly leads to bacterial death [ 12 ].…”

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications

“…Lantibiotics, a type of modified peptides, are promising candidates to fight against resistant bacterial strains . MD simulations show that they preferentially bind to lipid II, the precursor in the peptidoglycan biosynthetic pathway, and induce a water tunnel in the membrane …”

“…227 MD simulations show that they preferentially bind to lipid II, the precursor in the peptidoglycan biosynthetic pathway, and induce a water tunnel in the membrane. 228 Overall, the research landscape of AMPs requires (i) structural characterizations of the usually short peptide, which does not have an experimental structure, so MD simulations can be used to validate the predicted structure and study the structural change under different environmental conditions including pH; 229 (ii) an atomistic or near-atomistic picture of peptide-membrane interactions, and (iii) rationales about peptide targeting and cell selectivity based on cell membrane compositions. All of the above can be studied through Membrane Builder and Martini Maker in CHARMM-GUI.…”