Pathogens are constantly exposed to a variety of environmental stimuli, originating from their host, the microbiome, food, antibiotics, and other drugs. Adaptation to their host niche requires the concerted expression of different stress response pathways, regulated by transcription factors and small RNAs (sRNAs). However, the external cues and chemical stimuli that trigger specific pathways are still largely elusive, as well as how these regulatory cascades impact bacterial virulence and sensitivity to antibiotics.

Here we aim to explore signals (stressors) and regulatory pathways controlling host adaptation and antibiotic sensitivity in the foodborne pathogen Campylobacter jejuni, the main cause of bacterial gastroenteritis. We designed a unique chemical-genomics approach with two time-resolved readouts, where we profile both growth and transcriptional response of a transcriptional reporter-strain library of ~30 sRNAs, global stress regulators, and effectors challenged with ~2400 host-related chemical stimuli (small molecules).

After profiling ~16000 interactions, we detected a higher sensitivity of C. jejuni to multiple human-targeted drugs previously not classified as antibiotics (~4% tested compounds inhibited growth) compared to another major intestinal pathogen, Salmonella enterica. These compounds show potential to be used as adjuvants in combination with standard antibiotic treatments against C. jejuni. In addition, preliminary data already show a few stressor-regulator pairs where the reporter expression appears to be modulated in the presence of the chemical compound, accounting for ~0,5% hit rate. The majority of the identified compounds, including several commonly taken drugs, activated the expression of the cmeABC major efflux pump of C. jejuni, which plays a crucial role in antibiotic resistance. Overall, our data highlight the impact of non-antibiotic drugs on C. jejuni growth and potentially on modulating its ability to resist antimicrobial treatments.