An Alternative Bactericidal Mechanism of Action for Lantibiotic Peptides That Target Lipid II

Abstract

Lantibiotics are polycyclic peptides containing unusual amino acids, which have binding specificity for bacterial cells, targeting the bacterial cell wall component lipid II to form pores and thereby lyse the cells. Yet several members of these lipid II-targeted lantibiotics are too short to be able to span the lipid bilayer and cannot form pores, but somehow they maintain their antibacterial efficacy. We describe an alternative mechanism by which members of the lantibiotic family kill Gram-positive bacteria by removing lipid II from the cell division site (or septum) and thus block cell wall synthesis.

Amphotericin primarily kills yeast by simply binding ergosterol

“…Interestingly, our results support the conclusion that sterol binding is also primarily responsible for the antifungal action of natamycin (21), and several antibacterial peptides exert their effects via specific lipid binding as well (44)(45)(46)(47). Collectively, these findings suggest that the potential generality of this mode of action is substantial.…”

“…Thus, as accelerating advances in lipid biology continue to illuminate many specific lipids that are required for microbial cell physiology (48), such lipids can be viewed as promising new targets in the search for superior antimicrobials that may be less vulnerable to resistance. It is also likely that the possession of a dual mode of action, i.e., lipid binding and membrane permeabilization, which also appears to be more general (46), further contributes to the resistance-refractory nature of AmB. Gaining a more advanced understanding of how all of these processes are related at the molecular level thus also represents a frontier challenge of substantial importance.…”

Polyene antibiotic that inhibits membrane transport proteins

“…Amphotericin B may therefore be a good example of a polyene antibiotic that, via the binding of ergosterol, has a dual mode of action by inhibiting membrane proteins and permeabilizing the plasma membrane. A similar dual mode of action has been observed before in antibacterial lantibiotics that are able to block cell wall synthesis and form pores (27,28). Likewise, the antibiotics chloramphenicol and tetracycline were shown to act both by inhibiting protein synthesis and by blocking protein translocation into the bacterial membrane (29)(30)(31).…”

Focal targeting by human β-defensin 2 disrupts localized virulence factor assembly sites in Enterococcus faecalis

“…However, some CAMPs have additional targets that facilitate their toxic effects (40). Particularly well studied are peptides that interact specifically with the peptidoglycan biosynthesis intermediate lipid II at high affinity, including the lantibiotic nisin, fungal defensin plectasin, human neutrophil peptides, and hBD3, allowing them to "dock" at sites of cell-wall synthesis resulting in the sequestration of lipid II away from its functional location and/or resulting in localized membrane pore formation (22,(41)(42)(43)(44)(45). Because nascent PG synthesis, and hence lipid II appearance, occurs in rings emanating from the septal area in ovococci such as E. faecalis, it would not be surprising for lipid II targeting CAMPs to localize to the septal area, as we observe.…”