Detailed SAR and PCA of the tyrocidines and analogues towards leucocin A-sensitive and leucocin A-resistant Listeria monocytogenes.

Abstract

The tyrocidines, antimicrobial cyclic decapeptides from Bacillus aneurinolyticus, have potent activity with drug/disinfectant potential, specifically against Listeria monocytogenes. The tyrocidine activity is dependent on an amphipathic balance. Structure-activity relationship (SAR) analysis combined with principal component analysis showed the best activity correlation with hydropathy and solvent accessible volume (hydrophobicity parameters), Mr and molecular volume (steric/size parameters), coupled with rigid sequence and charge prerequisites. For potent activity against L. monocytogenes strains, there is a prerequisite for a Tyr or Phe in the (W/F)(w/f)NQ(Y/F/W) sequence of the variable pentapeptide and ornithine (Orn, O) as cationic residue in the conserved V(K/O)LfP pentapeptide, particularly with Trp in the aromatic dipeptide moiety of the variable pentapeptide. The roles of Trp and Orn in the tyrocidines were confirmed with most active peptide, tyrocidine B (TrcB) containing Orn and a Trp-D-Phe in the aromatic dipeptide moiety. However, a novel analogue with a trimethylated ornithine and Phe-D-Phe showed an activity rivalling that of TrcB. Our results emphasized that activity is dictated by interplay between the character of the aromatic residues in the variable pentapeptide and the cationic residue. Any residue change resulting in tighter membrane/cell wall interaction is likely to trap tyrocidines and impede their mechanism of action.