Modulating the development of E. coli biofilms with 2-aminoimidazoles.

The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC(50) of 13µM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400µM.

The chemical synthesis and antibiotic activity of a diverse library of 2-aminobenzimidazole small molecules against MRSA and multidrug-resistant A. baumannii.

Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein is described the development of a class of novel 2-aminobenzimidazoles with antibiotic activity. These active 2-aminobenzimidazoles retain their antibiotic activity against several strains of multidrug-resistant Staphylococcus aureus and Acinetobacter baumannii when compared to susceptible strains.

Antibiofilm activity of a diverse oroidin library generated through reductive acylation.

A diverse 20-compound library of analogues based on the marine alkaloid oroidin were synthesized via a reductive acylation strategy. The final target was then assayed for inhibition and dispersion activity against common proteobacteria known to form biofilms. This methodology represents a significant improvement over the generality of known methods to acylate substrates containing 2-aminoimidazoles and has the potential to have broad application to the synthesis of more advanced oroidin family members and their corresponding analogues.

Effects of N-pyrrole substitution on the anti-biofilm activities of oroidin derivatives against Acinetobacter baumannii.

Bacteria of the genus Acinetobacter spp. are rapidly emerging as problematic pathogens in healthcare settings. This is exacerbated by the bacteria's ability to form robust biofilms. Marine natural products incorporating a 2-aminoimidazole (2-AI) motif, namely from the oroidin class of marine alkaloids, have served as a unique scaffold for developing molecules that have the ability to inhibit and disperse bacterial biofilms. Herein we present the anti-biofilm activity of a small library of second generation oroidin analogues against the bacterium Acinetobacter baumannii.

Small molecule suppression of carbapenem resistance in NDM-1 producing Klebsiella pneumoniae.

The already considerable global public health threat of multi-drug resistant Gram-negative bacteria has become even more of a concern following the emergence of New-Delhi metallo-ß-lactamase (NDM-1) producing strains of Klebsiella pneumoniae and other Gram-negative bacteria. As an alternative approach to the traditional development of new bactericidal entities, we have identified a 2-aminoimidazole derived small molecule that acts as an antibiotic adjuvant and is able to suppress resistance of a NDM-1 producing strain of K. pneumoniae to imipenem and meropenem, in addition to suppressing resistance of other ß-lactam non-susceptible K. pneumoniae strains. The small molecule is able to lower carbapenem minimum inhibitory concentrations by up to 16-fold while exhibiting little bactericidal activity itself.