Abstract
The compounds referred to as bis(tryptophan)s (BTs) have shown activity as antimicrobials. 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 (H2N-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.
Highlights
Numerous reports have appeared warning of the increasing threat of illnesses caused by antibiotic-resistant bacteria [1]
Our hypothesis was that these amphiphiles insert into bacterial membranes and both increase permeability and affect such enzymes as efflux pumps
Could evidence be developed to support either or both of these assumptions? Second, was the formation of membraneactive amphiphiles based on amino acid head groups possible with any of the other common amino acids? We attempted to resolve the first question by using the planar bilayer voltage clamp experiment and fluorescence techniques
Summary
Numerous reports have appeared warning of the increasing threat of illnesses caused by antibiotic-resistant bacteria [1]. Natural amphiphiles [9] (often peptides [10]) such as colistin [11] and daptomycin are highly effective at inhibiting bacterial growth Their use has generally been limited owing to toxicity, but the rise in antibiotic resistance has increased demand for them [12]. The hydraphiles were designed as channels that would be active in bilayer membranes and their function as such has been fully characterized and reported [31] Both classes of compounds exhibit antimicrobial properties and both classes of compounds function as potency-enhancing adjuvants for common antibacterials to which organisms have become resistant [32,33]. We report additional antimicrobial studies, the membrane activity of several BTs, insight into the mechanism of action of these bis(tryptophan)s, and a group of new bis(amino acid)s
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call