Highly Active Modulators of Indole Signaling Alter Pathogenic Behaviors in Gram-Negative and Gram-Positive Bacteria

Indole is a universal signal that regulates various bacterial behaviors, such as biofilm formation and antibiotic resistance. To generate mechanistic probes of indole signaling and control indole‐mediated pathogenic phenotypes in both Gram‐positive and Gram‐negative bacteria, we have investigated the use of desformylflustrabromine (dFBr) derivatives to generate highly active indole mimetics. We have developed non‐microbicidal dFBr derivatives that are 27–2000 times more active than indole in modulating biofilm formation, motility, acid resistance, and antibiotic resistance. The activity of these analogues parallels indole, because they are dependent on temperature, the enzyme tryptophanase TnaA, and the transcriptional regulator SdiA. This investigation demonstrates that molecules based on the dFBr scaffold can alter pathogenic behaviors by mimicking indole‐signaling pathways. Phenotype control: Non‐microbicidal desformylflustrabromine (dFBr) derivatives that are 27‐2000 times more active than indole in modulating biofilm formation, motility, acid resistance, and antibiotic resistance were developed. This investigation demonstrates that molecules based on the dFBr scaffold can alter pathogenic behaviors by mimicking indole‐signaling pathways (see scheme).