Sensitivity of Antibacterial Activity to Backbone Sequence in Constitutionally Isomeric OligoTEAs.

Antimicrobial peptides are promising alternatives to traditional antibiotics but their translational potential is limited due to rapid degradation by serum proteases. Recently, a number of peptidomimetics with backbones resistant to proteolysis have been synthesized and their antimicrobial potential evaluated as a function of their hydrophobic to cationic ratio. However, these mimetics also have a fixed backbone thus making it difficult to isolate the effect of backbone hydrophobic composition and sequence. In this work, advantage is taken of the oligothioetheramide (oligoTEA) synthetic strategy that allows for precise control over backbone and pendant group placement to systematically study the effect of backbone hydrophobic sequence while keeping pendant group constant. Biophysical data acquired with a set of constitutional oligoTEA isomers show that backbone hydrophobic sequence, that is, local hydrophobicity, affects the mode of oligoTEA interaction with lipid bilayers. This differential interaction among the constitutionally isomeric oligoTEAs is manifested in their antibacterial activities and points to the possibility of using backbone hydrophobic sequence to tune antibacterial potency and selectivity.