Antimicrobial peptides: their role as infection-selective tracers for molecular imaging

Abstract

Antimicrobial peptides (AMPs) are a heterogeneous class of compounds found in a variety of organisms including humans and, so far, hundreds of these structures have been isolated and characterised. They can be described as natural microbicide, selectively cytotoxic to bacteria, whilst showing minimal cytotoxicity towards the mammalian cells of the host organism. They act by their relatively strong electrostatic attraction to the negatively charged bacterial cells and a relatively weak interaction to the eukaryote host cells. The ability of these peptides to accumulate at sites of infection combined with the minimal host's cytotoxicity motivated for this review to highlight the role and the usefulness of AMPs for PET with emphasis on their mechanism of action and the different interactions with the bacterial cell. These details are key information for their selective properties. We also describe the strategy, design, and utilization of these peptides as potential radiopharmaceuticals as their combination with nuclear medicine modalities such as SPECT or PET would allow noninvasive whole-body examination for detection of occult infection causing, for example, fever of unknown origin.

Figure 1

Membrane targeting of antimicrobial peptides and basis of their selectivity (adapted from [45]).

Figure 2

Comparative lipid architecture of microbial and human cytoplasmic membranes. Cytoplasmic membranes of bacterial (Escherichia coli, Staphylococcus aureus, or Bacillus subtilis) and fungal (Candida albicans) pathogens are compared with that of the human erythrocyte in relative composition and distribution between inner and outer membrane leaflets. Membrane constituents ranging from anionic (left) to neutral (right) are CL, PG, PE, PC, SM, and sterols (cholesterol or ergosterol, ST). Note the marked difference among microbial pathogens and human erythrocytes resides in the phospholipid composition and asymmetry. These differences are believed to account for the selective antimicrobial peptide affinity for microbial versus host cells to the extent that it exists for a given antimicrobial peptide. Keys: open, E. coli; horizontal hatching, S. aureus; shaded, B. subtilis; checkered, C. albicans; solid, human erythrocyte (adapted from [9]).

Figure 3

Statistical analysis of residue distribution in the 20-residue N-terminal stretch α-helical AMPs from natural sources. A graphical representation of the frequency of different types of residue at each position on a helical wheel projection is shown. The uneven distribution of hydrophobic and charged peptides contributes to the amphipathic nature of the peptide (adapted from Tossi et al. [17]).

Figure 4

Overview of possible interaction mechanism following peptide interaction with the bacterial cell membrane [53], that is, (a) barrel-stave model (pore formation), (b) toroidal model (pore formation), and (c) carpet model (membrane disruption). Red coloured peptide regions: hydrophilic; blue coloured peptide regions: hydrophobic.

Figure 5

Approaches in radiolabeling of peptides. The direct method (a) where radionuclides are covalently attached to the peptide and the indirect method (b) where radionuclides are attached to targeting peptides by means of bifunctional chelators [8].

Figure 6

Primary structure of ubiquicidin as originally reported by Hiemstra and coworkers [49].

Figure 7

Anterior whole-body image taken at 30 min after tracer injection showing kidneys (dotted arrow), liver (solid arrow), and urinary bladder (ball arrow) (adapted from [52]).