@article{21928,
  abstract     = {Antibiotic combination in time and space is a key strategy to combat antimicrobial resistance. The success of such treatment designs requires their robust efficacy across treatment conditions and a pathogen’s genomic diversity. This study found that an initial treatment with a β-lactam antibiotic causes robust cellular sensitization towards an aminoglycoside antibiotic across the high-risk human pathogen Pseudomonas aeruginosa, including resistant strains. This phenomenon of cellular sensitization, termed negative hysteresis, is modulated by the Cpx envelope stress response system and linked to membrane stress during growth. The increase in efficacy is achieved through a β-lactam induced elevated cellular uptake of the subsequently administered aminoglycoside. Negative hysteresis and the Cpx system are linked in several cases to the expression of synergistic drug interactions, thus enhancing efficacy of antibiotic combinations. Overall, our study identifies the phenomenon of negative hysteresis as a robustly inducible phenotype and thus a unique focus for optimizing antimicrobial therapy.},
  author       = {Buchholz, Florian and Upterworth, Lina M. and Tueffers, Leif and Groth, Espen E. and Haas, Kira and Schütz, Daniel and Savietto Scholz, Abigail and Batra, Aditi and Pal, Surajit and Banerjee, Samarpita and Dubey, Badri N. and Franzenburg, Sören and Kalsdorf, Barbara and Rabe, Klaus F. and Nurjadi, Dennis and Rupp, Jan and Andersson, Dan I. and Sondermann, Holger and Bramkamp, Marc and Römhild, Roderich and Schulenburg, Hinrich},
  issn         = {2041-1723},
  journal      = {Nature Communications},
  publisher    = {Springer Nature},
  title        = {{Robust antibiotic sensitization of pathogenic Pseudomonas aeruginosa via negative hysteresis in the cell envelope}},
  doi          = {10.1038/s41467-026-71178-5},
  volume       = {17},
  year         = {2026},
}

@article{19626,
  abstract     = {Active regulation of gene expression, orchestrated by complex interactions of activators and repressors at promoters, controls the fate of organisms. In contrast, basal expression at uninduced promoters is considered to be a dynamically inert mode of nonfunctional “promoter leakiness,” merely a byproduct of transcriptional regulation. Here, we investigate the basal expression mode of the mar operon, the main regulator of intrinsic multiple antibiotic resistance in Escherichia coli, and link its dynamic properties to the noncanonical, yet highly conserved start codon of marR across Enterobacteriaceae. Real-time, single-cell measurements across tens of generations reveal that basal expression consists of rare stochastic gene expression pulses, which maximize variability in wildtype and, surprisingly, transiently accelerate cellular elongation rates. Competition experiments show that basal expression confers fitness advantages to wildtype across several transitions between exponential and stationary growth by shortening lag times. The dynamically rich basal expression of the mar operon has likely been evolutionarily maintained for its role in growth homeostasis of Enterobacteria within the gut environment, thereby allowing other ancillary gene regulatory roles to evolve, e.g., control of costly-to-induce multidrug efflux pumps. Understanding the complex selection forces governing genetic systems involved in intrinsic multidrug resistance is crucial for effective public health measures.},
  author       = {Jain, Kirti and Hauschild, Robert and Bochkareva, Olga and Römhild, Roderich and Tkačik, Gašper and Guet, Calin C},
  issn         = {1091-6490},
  journal      = {Proceedings of the National Academy of Sciences},
  number       = {15},
  publisher    = {National Academy of Sciences},
  title        = {{Pulsatile basal gene expression as a fitness determinant in bacteria}},
  doi          = {10.1073/pnas.2413709122},
  volume       = {122},
  year         = {2025},
}