Abstract
Antimicrobial peptides (AMPs) have remarkably different structures as well as biological activity profiles, whereupon most of these peptides are supposed to kill bacteria via membrane damage. In order to understand their molecular mechanism and target cell specificity for Gram-positive bacteria, it is essential to consider the architecture of their cell envelopes. Before AMPs can interact with the cytoplasmic membrane of Gram-positive bacteria, they have to traverse the cell wall composed of wall- and lipoteichoic acids and peptidoglycan. While interaction of AMPs with peptidoglycan might rather facilitate penetration, interaction with anionic teichoic acids may act as either a trap for AMPs or a ladder for a route to the cytoplasmic membrane. Interaction with the cytoplasmic membrane frequently leads to lipid segregation affecting membrane domain organization, which affects membrane permeability, inhibits cell division processes or leads to delocalization of essential peripheral membrane proteins. Further, precursors of cell wall components, especially the highly conserved lipid II, are directly targeted by AMPs. Thereby, the peptides do not inhibit peptidoglycan synthesis via binding to proteins like common antibiotics, but form a complex with the precursor molecule, which in addition can promote pore formation and membrane disruption. Thus, the multifaceted mode of actions will make AMPs superior to antibiotics that act only on one specific target.
Highlights
For many years, the World Health Organization has emphasized the high proportions of antibiotic resistance in bacteria causing common infections such as pneumonia, urinary tract and blood stream infections in all regions of the world
It was concluded that in order to proliferate, L-form bacteria compromise the loss of cell wall by intercalation of amphipathic molecules like fatty acids into the bilayer to increase the surface area above the internal volume of the cell that directly drives the shape distortion leading to vesicle fission
In contrast to many antibiotics that exhibit their antimicrobial activity via binding to and inhibition of enzymes involved in PGN biosynthesis, antimicrobial peptides (AMPs) bind to peptidoglycan precursors and in turn interfere with further enzymatic processes resulting in inhibition of PGN synthesis by sterically hindering the activity of enzymes [140]
Summary
The World Health Organization has emphasized the high proportions of antibiotic resistance in bacteria causing common infections such as pneumonia, urinary tract and blood stream infections in all regions of the world. Their global report on surveillance in 2014 referred to alarming levels in bacterial resistance in many parts of the world and the urgent need to develop a global intervention plan against antimicrobial resistance [1]. The number of new antibiotics steadily decreased and only recently two novel antibiotics, the antimicrobial lipopeptides daptomycin and oritavancin, were approved by the FDA for the treatment of severe infections caused by Gram-positive bacteria. As numerous reviews exist on membrane damaging activities of AMPs (e.g., [44] and references therein), we will not discuss in depth those mechanistic backgrounds but rather delineate mode of actions that may be relevant for Gram-positive bacteria with an emphasis on the diverse nature of bacterial cell envelopes of Gram-positive and Gram-negative bacteria
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