The antibiotic NAB815 does not induce SOS response and toxin production in Shiga toxin-producing Escherichia coli at sub-bactericidal concentrations.
TL;DR
It is demonstrated that exposure of reporter or wild type clinical STEC strains to NAB815 neither triggered the SOS response nor increased Stx1 or Stx2 amounts, indicating that NAB815 may mitigate Stx-mediated toxicity without having an off-target effect on Stx phage activation.
Abstract
Hemolytic uremic syndrome (HUS) is a rare but severe clinical condition, primarily caused by Shiga toxin-producing Escherichia coli (STEC) infections. A critical early step in the pathogenesis of HUS is the entry of Shiga toxins (Stx) into the bloodstream, where they interact with circulating blood cells via globotriaosylceramide (Gb3Cer) and Toll-like receptor 4 (TLR4). This triggers the release of Stx-containing extracellular vesicles (EV), a critical late step for HUS onset. Currently, there are no specific therapeutic interventions for HUS, and the management of STEC-infected patients is largely supportive. Antibiotics are generally avoided due to the risk of inducing the bacterial SOS response thereby enhancing Stx phage activation and toxin production. Recently, our group developed NAB815, a polymyxin B derivative capable of inhibiting Stx2a binding to TLR4, thereby reducing the release of Stx-containing EV and enhancing survival in cellular and animal models. However, as NAB815 is an antibiotic, it is unclear whether it might also have an undesirable impact on Stx production via phage activation. Here, we demonstrate that exposure of reporter or wild type clinical STEC strains to NAB815 neither triggered the SOS response nor increased Stx1 or Stx2 amounts. These results indicate that NAB815 may mitigate Stx-mediated toxicity without having an off-target effect on Stx phage activation, supporting its potential as a safe therapeutic intervention for STEC patients.