Human-targeted drugs extensively reshape regulatory networks controlling virulence and antibiotic resistance in Salmonella Typhimurium
- 1Interfaculty Institute of Microbiology and Infection Medicine Tuebingen (IMIT), University of Tuebingen, Tuebingen, Germany
Abstract
Human-targeted drugs are increasingly recognized to affect bacterial physiology, yet their impact beyond growth inhibition, and the underlying molecular mechanisms, remain poorly understood. Here, we systematically mapped how chemically diverse host-associated compounds influence virulence and intrinsic antibiotic resistance in Salmonella enterica serovar Typhimurium. Using a high-throughput reporter approach, we quantified transcriptional response of 26 key stress promoters in Salmonella against 2,415 compounds, including FDA-approved drugs, food-derived molecules, and human metabolites. We found that non-antibiotic compounds induce transcriptional responses distinct from those elicited by antibiotics, uncovering a regulatory shift from general stress responses to compound-specific regulation driven by ligand-responsive MarR- and TetR-family regulators. In particular, more than 200 non-antibiotic drugs modulate virulence or intrinsic resistance pathways through the central regulators SlyA or RamR, respectively. By integrating our large-scale dataset with machine learning, we further defined chemical features associated with ramA transcriptional activation in Salmonella, and predicted ~200 additional candidate inducers of intrinsic antibiotic resistance in this pathogen. Together, our results uncovered a large and previously unrecognized chemical landscape that reshapes bacterial stress responses through ligand-responsive regulatory mechanisms, with implications for how host-associated compounds influence pathogen virulence and antibiotic resistance.
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BibTeX
@misc{amstalden2026humantargeted,
title = {{Human-targeted drugs extensively reshape regulatory networks controlling virulence and antibiotic resistance in Salmonella Typhimurium}},
author = {M. K. Amstalden and R. Olayo-Alarcon and S. Brenzinger and L. Debande and A. Zannoni and E. Fiore and A. Boudrioua and A. Rashidian and T. Kronenberger and S. Wagner and C. M. Sharma and C. L. Mueller and A. R. Brochado},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755304},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755304v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Human-targeted drugs extensively reshape regulatory networks controlling virulence and antibiotic resistance in Salmonella Typhimurium
AU - M. K. Amstalden
AU - R. Olayo-Alarcon
AU - S. Brenzinger
AU - L. Debande
AU - A. Zannoni
AU - E. Fiore
AU - A. Boudrioua
AU - A. Rashidian
AU - T. Kronenberger
AU - S. Wagner
AU - C. M. Sharma
AU - C. L. Mueller
AU - A. R. Brochado
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755304
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755304v1
AB - Human-targeted drugs are increasingly recognized to affect bacterial physiology, yet their impact beyond growth inhibition, and the underlying molecular mechanisms, remain poorly understood. Here, we systematically mapped how chemically diverse host-associated compounds influence virulence and intrinsic antibiotic resistance in Salmonella enterica serovar Typhimurium. Using a high-throughput reporter approach, we quantified transcriptional response of 26 key stress promoters in Salmonella against 2,415 compounds, including FDA-approved drugs, food-derived molecules, and human metabolites. We found that non-antibiotic compounds induce transcriptional responses distinct from those elicited by antibiotics, uncovering a regulatory shift from general stress responses to compound-specific regulation driven by ligand-responsive MarR- and TetR-family regulators. In particular, more than 200 non-antibiotic drugs modulate virulence or intrinsic resistance pathways through the central regulators SlyA or RamR, respectively. By integrating our large-scale dataset with machine learning, we further defined chemical features associated with ramA transcriptional activation in Salmonella, and predicted ~200 additional candidate inducers of intrinsic antibiotic resistance in this pathogen. Together, our results uncovered a large and previously unrecognized chemical landscape that reshapes bacterial stress responses through ligand-responsive regulatory mechanisms, with implications for how host-associated compounds influence pathogen virulence and antibiotic resistance.
ER -