Biomimetic Facially Amphiphilic Antibacterial Oligomers with Conformationally Stiff Backbones

Abstract

A foldamer has been designed with a conformationally stiff backbone that is facially amphiphilic. The oligomer has excellent antimicrobial activity and was found to be 18 times more active toward bacterial cells than human red blood cells. The oligomer is built from arylamide bonds around a central 4,6-dicarboxy pyrimidine ring. The conformation was studied by X-ray crystallography and solution NMR spectroscopy. Density-functional (DFT) calculations were performed to guide the design. These calculations accurately predicted the overall conformation as well as NMR chemical shifts. Antibacterial activity was demonstrated against E. coli, a gram-negative strain, and B. subtilis, a gram-positive strain. The minimal inhibitory concentration is 0.8 microg/ml.

De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers

“…The effect of guanidine for amine replacements of 4,6-disubstituted arylamide foldamers Table 3. The effect of guanidinylation of 5-monosubstituted arylamide foldamers substituents in 4c (24), prompting the synthesis of pyrimidinecontaining compound 6d. In vitro, compounds 6c and 6d were highly activity against a variety of Gram-positive and Gramnegative bacteria (Table 4).…”

“…A number of studies reported antibiotics designed to follow the mechanism of natural AMPs, for example, peptides composed of ␣-amino acids (15)(16)(17), ␤-amino acids (18,19), peptoids (20), aromatic oligomers (21)(22)(23)(24), and synthetic polymers (25)(26)(27). Previously, we designed a series of arylamide foldamers that showed potential for both activity and selectivity (21).…”

Conformationally rigid proteomimetics: a case study in designing antimicrobial aryl oligomers

“…5A and B). 12 It is obvious that the structure without the central pyrimidine ring (Fig. 5B) was not confined to the linear conformation.…”

“…12 The pyrimidine arylamide with three rings (Fig. 5C) had an MIC of 0.8 lg mL −1 compared to its non-pyrimidine analogue which had an MIC of 12 lg mL −1 .…”

“…5). 12 In this design the two additional nitrogen atoms provided new hydrogen bond acceptors, resulting in a 3-centered hydrogen bond, 35,36 that limited rotation around the aromatic carbon-carbonyl bond which was not confined in the first set of arylamide oligomers studied (Fig. 3).…”