Intracellular Targets of Antibacterial Peptides

Abstract

The recent past witnessed a decrease in the number of new antibacterial compounds approved by the regulatory agencies and an almost complete lack of molecules killing bacteria by novel mechanisms of action. The broad spectrum antimicrobial agents currently on the market carry the potential, and indeed victims, of resistance developed against them. The need for new types of antimicrobial drugs coincides with the desire of developing lead molecules that act selectively on a single strain, or perhaps on a few closely related strains. Such selectivity would exclude the likelihood of the emergence of broad-range resistance. Intracellular bacterial targets most prevalently proteins needed for the life cycle of bacteria, carry the potential to be a resourceful target for a new family of antimicrobial compounds. Inhibition of proteinaceous functions requires stereospecificity, and a drug structurally similar to the target proteins themselves. Indeed, some antibacterial peptides show selective inhibition of intracellular targets. A few native peptides and their designed analogs appear to kill only a limited number of bacterial strains. Identification of the binding sites on the target proteins would allow the design of strain-specific antibacterial and antifungal peptides without the fear of development of common resistance to these agents.

Investigation into the mechanism of action of the antimicrobial peptides Os and Os-C derived from a tick defensin

“…These results point towards membrane acting peptides which may have additional intracellular targets such as DNA. Further studies are necessary to identify other possible intracellular targets, for example, stimulation of autolytic enzymes or inhibition of other proteins essential to the bacterial life cycle [8]. The differences between Os and Os-C, such as the more effective permeabilization of membranes at lower concentrations and binding of Os to DNA, and the accumulation of labeled Os-C on B. subtilis septa, suggest that the two peptides do not act in the same manner.…”

“…However, AMPs which do not kill by permeabilization may kill through a wide range of intracellular mechanisms [14]. Some intracellular targets include the stimulation of autolytic enzymes, the inhibition of DNA synthesis, protein synthesis, cell wall and membrane synthesis [8,15]. The use of microscopy may reveal important insights into the killing mechanism.…”

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).…”

“…Some of them have been identified in mammal neutrophils (7), whereas others have been found in hemolymph of insects and crustaceans (8). All of them invariably have a high number of proline and arginine residues, show similar spectra of activity, including several Gram-negative species, and have similar modes of action.…”

Different modes of antibiotic action of homodimeric and monomeric bactenecin, a cathelicidin-derived antibacterial peptide

“…In the case of the former, membrane-targeting antibacterial peptides aggregate on the surface of bacterial cells and then penetrate into the lipid membrane to form transmembrane channels or pores (7,8). In the case of latter, the peptides penetrate all the way through the membrane and then inhibit various intracellular functions, including cell wall, nucleic acid and protein synthesis (9). Interestingly, recent findings suggest that the bactericidal effects of some antibacterial peptides involve a dual mode of action: membrane disruption coupled to secondary intracellular targeting (10,11).…”