Thanatin: An Emerging Host Defense Antimicrobial Peptide with Multiple Modes of Action

Abstract

Antimicrobial peptides (AMPs) possess great potential for combating drug-resistant bacteria. Thanatin is a pathogen-inducible single-disulfide-bond-containing β-hairpin AMP which was first isolated from the insect Podisus maculiventris. The 21-residue-long thanatin displays broad-spectrum activity against both Gram-negative and Gram-positive bacteria as well as against various species of fungi. Remarkably, thanatin was found to be highly potent in inhibiting the growth of bacteria and fungi at considerably low concentrations. Although thanatin was isolated around 25 years ago, only recently has there been a pronounced interest in understanding its mode of action and activity against drug-resistant bacteria. In this review, multiple modes of action of thanatin in killing bacteria and in vivo activity, therapeutic potential are discussed. This promising AMP requires further research for the development of novel molecules for the treatment of infections caused by drug resistant pathogens.

Keywords: antimicrobial peptides (AMPs); lipopolysaccharide (LPS); mechanism of AMPs; multidrug-resistant (MDR) bacteria; thanatin.

Figure 1

Amino acid sequences of thanatin and brevinin-1. The central Thr residue in the disulfide loop of thanatin is highlighted in green. Cys residues are indicated in blue.

Figure 2

Structures of thanatin in lipopolysaccharide (LPS, pdb:5xo9) and dodecyl phosphocholine (DPC) (pdb: 6aab) micelles. Thanatin forms a dimeric structure in LPS micelles. The side chains of (A) Y10/Y10′, M21/M21′, and (B) I9/I9′ demonstrated packing interactions in the antiparallel β-sheet topology. (C) Electrostatic potential surface of dimeric thanatin. (D) Monomeric β-hairpin structure of thanatin in DPC micelles. The β-sheet is shown as a ribbon. The figure was prepared using PyMOL.

Figure 3

Molecular dynamics (MD) simulation of the interactions between LPS and thanatin. Left panel: time course of the binding of thanatin to LPS in a bilayer observed in the simulation. Right panel: interactions of residues of thanatin with LPS head groups [27].

Figure 4

Structure (pdb: 6GD5) of thanatin in complex with LptA_m: (A) The 3-D topology of the complex showing the β-sheet jelly-roll fold (purple) of LptA_m and the β-hairpin of thanatin (in green). The side chains of residues of thanatin are shown as sticks. (B) Potential ionic interactions of residues R13 and R14 of thanatin with residues E39 and D41 of LptA_m. (C) Packing interactions of residues Y10, I8 of thanatin with hydrophobic-pocket residues F54 and V70 of LptA_m.