Restoring Antibiotic Sensitivity via Metabolic Pathway Manipulation in Pseudomonas aeruginosa
- 1Imperial College London; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Abstract
Stopping antimicrobial multidrug resistance (AMR) is essential to maintain the efficacy of current treatments and sustain modern medicine, but current control relies on a coordinated One Health approach involving stewardship, infection prevention and other control measures, without direct actionable mechanisms against resistance itself. Here, integrating proteomics and metabolomics with high-throughput Caenorhabditis elegans infection models, we show that unique synergy of biotin biosynthesis inhibition with metformin uncouples virulence from bacterial viability shutting down major Pseudomonas aeruginosa (PA) virulence mechanisms that impair host survival. Under directed evolution induced by central carbon metabolic stress, laboratory and clinical PA strain isolates acquire mutations in the MexAB-OprM multidrug efflux pump, leading to reversal of the AMR phenotype and restored susceptibility to multiple legacy and last-resort antibiotics such as meropenem. Our findings reveal a previously unexploited vulnerability in PA, its co-dependence on biotin biosynthesis and energy metabolism for virulence and resistance. This work establishes a conceptual framework in which metabolic co-targeting can abolish pathogenesis and drive reversal of antimicrobial resistance. It lays the foundation for first-in-class, non-antibiotic PA-selective anti-virulence and resistance-reversing therapies, key to extending the lifesaving duration of existing antibiotics.
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BibTeX
@misc{doherty2026restoring,
title = {{Restoring Antibiotic Sensitivity via Metabolic Pathway Manipulation in Pseudomonas aeruginosa}},
author = {H. M. Doherty and J. van der Laan and D. Martinez-Martinez and T. Fink and K. Stanzel and H. Ahmad and L. Helfer and A. Ivan and L. Game and I. Kaneva and A. Montoya and H. Kramer and J. Mokochinski and S. Brodesser and I. Sottorff and E. Bohn and T. Bollenbach and M. Banzhaf and F. Cabreiro},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755869},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755869v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Restoring Antibiotic Sensitivity via Metabolic Pathway Manipulation in Pseudomonas aeruginosa
AU - H. M. Doherty
AU - J. van der Laan
AU - D. Martinez-Martinez
AU - T. Fink
AU - K. Stanzel
AU - H. Ahmad
AU - L. Helfer
AU - A. Ivan
AU - L. Game
AU - I. Kaneva
AU - A. Montoya
AU - H. Kramer
AU - J. Mokochinski
AU - S. Brodesser
AU - I. Sottorff
AU - E. Bohn
AU - T. Bollenbach
AU - M. Banzhaf
AU - F. Cabreiro
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755869
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755869v1
AB - Stopping antimicrobial multidrug resistance (AMR) is essential to maintain the efficacy of current treatments and sustain modern medicine, but current control relies on a coordinated One Health approach involving stewardship, infection prevention and other control measures, without direct actionable mechanisms against resistance itself. Here, integrating proteomics and metabolomics with high-throughput Caenorhabditis elegans infection models, we show that unique synergy of biotin biosynthesis inhibition with metformin uncouples virulence from bacterial viability shutting down major Pseudomonas aeruginosa (PA) virulence mechanisms that impair host survival. Under directed evolution induced by central carbon metabolic stress, laboratory and clinical PA strain isolates acquire mutations in the MexAB-OprM multidrug efflux pump, leading to reversal of the AMR phenotype and restored susceptibility to multiple legacy and last-resort antibiotics such as meropenem. Our findings reveal a previously unexploited vulnerability in PA, its co-dependence on biotin biosynthesis and energy metabolism for virulence and resistance. This work establishes a conceptual framework in which metabolic co-targeting can abolish pathogenesis and drive reversal of antimicrobial resistance. It lays the foundation for first-in-class, non-antibiotic PA-selective anti-virulence and resistance-reversing therapies, key to extending the lifesaving duration of existing antibiotics.
ER -