Azaindole Based Potentiator of Antibiotics against Gram-Negative Bacteria

We discovered azaindole-based compounds with weak innate activity that exhibit substantial potentiation of antibacterial activities of different antibiotics, viz., rifampicin, erythromycin, solithromycin, and novobiocin in Gram-negative bacteria. In the presence of the azaindole derivatives, these antibiotics exhibited submicromolar minimum inhibitory concentrations (MICs) against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. The fold improvements in MIC of these antibiotics that were otherwise weak or inactive on their own against these bacteria were also observed against drug-resistant clinical isolates. Our studies indicate that this selective potentiation is probably through destabilization of the outer membrane's integrity, known to be regulated by the lipopolysaccharides (LPS). Thus, the azaindole based compounds described here open opportunities for those antibiotics that are otherwise ineffective due to LPS mediated entry barriers in Gram-negative bacteria.

Automated summary

Azaindole-based compounds are able to potentiate the antibacterial activities of different antibiotics in Gram-negative bacteria, especially against bacteria that are otherwise weak or inactive against these antibiotics. These compounds may selectively enhance the antibiotic activities by destabilizing the integrity of the outer membrane, overcoming the entry barriers regulated by lipopolysaccharides.