5-Nitroimidazole ethers boost anti-Helicobacter pylori activity via a dual mode of action and effectively eradicate infections in vivo

ABSTRACT: Metronidazole (Metro) represents the front line-drug against Helicobacter pylori infections, but despite its crucial role as an antibiotic, little is known about its exact mode of action (MoA). To unravel cellular protein targets, we here performed activity-based protein profiling (ABPP) with tailored Metro probes. Surprisingly, an alkynylated ether probe (Metro-P3) exhibited a 60-fold enhanced potency against H. pylori, suggesting that this moiety represents a crucial, yet undiscovered switch for the activity profile. ABPP in living H. pylori uncovered two major protein targets, chaperonin HpGroEL and thiol peroxidase HpTpx, which are both part of the oxidative stress response and essential for H. pylori to survive under gastric oxidative stress. Tailored biological assays validated the inhibition of both targets by covalent modification of cysteines. Strikingly, the binding of Metro-P3 to HpTpx was much more pronounced compared to the parent drug. This diverging interaction of both molecules was corroborated by co-crystallization studies with Metro and Metro-P3 identifying the propargyl ether moiety to be essential for a prominent helix-dipole interaction in HpTpx. Metro-P3 along with several refined ether analogs exhibited no human cell toxicity up to 1 mM, favorable pharmacological profiles, and sufficient plasma stability. Satisfyingly, the activity boost translated to in vivo H. pylori mouse infection models where the most potent ether analog showed full eradication of bacteria at 50-fold reduced dosing compared to regular metronidazole standard triple therapy. Overall, our results highlight ether modifications of 5-nitroimidazole alcohols as unprecedented path towards dual MoA antibiotics which induce oxidative stress and simultaneously inhibit the stress response eventually leading to bacterial cell death

INSTRUMENT(S):

ORGANISM(S): Helicobacter Pylori 26695

DISEASE(S): Bacterial Infectious Disease,Bacterial Gastritis

SUBMITTER: Nina Bach  

LAB HEAD: Stephan Axel Sieber

PROVIDER: PXD051773 | Pride | 2026-04-13

REPOSITORIES: Pride