Non-Membrane Permeabilizing Modes of Action of Antimicrobial Peptides on Bacteria

Abstract

Antimicrobial peptides (AMPs) are a large class of innate immunity effectors with a remarkable capacity to inactivate microorganisms. Their ability to kill bacteria by membranolytic effects has been well established. However, a lot of evidence points to alternative, non-lytic modes of action for a number of AMPs, which operate through interactions with specific molecular targets. It has been reported that non-membrane-permeabilizing AMPs can bind to and inhibit DNA, RNA or protein synthesis processes, inactivate essential intracellular enzymes, or affect membrane septum formation and cell wall synthesis. This minireview summarizes recent findings on these alternative, non-lytic modes of antimicrobial action with an emphasis to the experimental approaches used to clarify each step of their intracellular action, i.e. the cell penetration mechanism, intracellular localization and molecular mechanisms of antibacterial action. Despite the fact that such data exists for a large number of peptides, our analysis indicates that only for a small number of AMPs sufficient data have been collected to support a mode of action with an authentic and substantial contribution by intracellular targeting. In most cases, peptides with non-lytic features have not been thoroughly analyzed, or only a single aspect of their mode of action has been taken into consideration and therefore their mechanism of action can only be hypothesized. A more detailed knowledge of this class of AMPs would be important in the design of novel antibacterial agents against unexploited targets, endowed with the capacity to penetrate into pathogen cells and kill them from within.

The Mechanism of Killing by the Proline-Rich Peptide Bac7(1–35) against Clinical Strains of Pseudomonas aeruginosa Differs from That against Other Gram-Negative Bacteria

“…Bac7 and its BODIPY fluorescently labeled derivative [Bac7 -BY] were prepared as previously described (14). Bac5(1-31) and BMAP27 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) were chemically synthesized as previously described (41). Apidaecin 137 and oncocin 112 were generously provided by Ralf Hoffmann (13,42).…”

“…Most AMPs strongly interact with bacterial membranes, leading to a lethal permeabilization of the microbial envelope (2). However, some AMPs kill bacteria mainly by interfering with internal cellular functions and without significant perturbation of cell membranes at microbicidal concentrations (3,4).…”

Antimicrobial Peptides: Mechanisms of Action and Resistance

“…Finally, it should be mentioned that the properties and sequences of many AMPs resemble those of cell-penetrating peptides (Pärn et al 2015 ; Table 1) and that they may enter the cell before membrane rupture occurs. Once the peptides reach the cell interior, they may also interact with proteins, nucleic acids, and cellular organelles, which by itself constitutes a potential cell-killing mechanism (Scocchi et al 2016).…”

“…As described above, cationic AMPs employ multiple modes of action (Scocchi et al 2016), and bacteria that become resistant to 1 AMP may or may not become resistant to AMPs from a different functional class (Table 2). Moreover, we recently found that even subtle structural changes to an AMP can alter bacterial resistance.…”

Antimicrobial peptides as natural bio-preservative to enhance the shelf-life of food

“…4). Various researchers investigated that few antimicrobial peptides enter inside the cell without the disruption of cell membrane and cell wall and targets the nucleic acids such as DNA, RNA (Zhao et al 2015;Scocchi et al 2016). Certain antimicrobial peptides inhibit the DNA synthesis, do not form the septum of the membrane.…”