Bis(Tryptophan) amphiphiles form ion conducting pores and enhance antimicrobial activity against resistant bacteria

Abstract

The compounds referred to as bis(tryptophan)s (BTs) have shown activity as antimicro-bials. The hypothesis that the activity of these novel amphiphiles results from insertion in bilayer membranes and transport of cations is supported by planar bilayer voltage-clamp studies reported herein. In addition, fluorescence studies of propidium iodide penetration of vital bacteria confirmed enhanced permeability. It was also found that BTs having either meta-phenylene or n-dodecylene linkers function as effective adjuvants to enhance the properties of FDA-approved antimicrobials against organisms such as S. aureus. In one example, a BT-mediated synergistic effect enhanced the potency of norfloxacin against S. aureus by 128-fold. In order to determine if related compounds in which tryptophan was replaced by other common amino acids (H2 N-Aaa-linker-Aaa-NH2) we active, a family of analogs have been prepared, characterized, and tested as controls for both antimicrobial activity and as adjuvants for other antimicrobials against both Gram-negative and Gram-positive bacteria. The most active of the compounds surveyed remain the bis(tryptophan) derivatives.