Novel Drug-like HsrA Inhibitors Exhibit Potent Narrow-Spectrum Antimicrobial Activities against Helicobacter pylori

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase of multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide, encouraging scientific community to discover and develop new antimicrobial strategies. In the present work, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against antibiotic-resistant strains of H. pylori. Most of these novel antimicrobials exhibited minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, additive effect in combination with metronidazole and clarithromycin, as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggested that in vivo inhibition of HsrA triggered lethal global disturbances in H. pylori physiology, including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori.