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Article

Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic

1
Department of Molecular Genetics, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
2
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
3
Groningen Biomolecular Science & Biotechnology Institute, University of Groningen, Nijenborg 4, 9747 AG Groningen, The Netherlands
4
Medical Imaging Center, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
*
Authors to whom correspondence should be addressed.
Academic Editor: Michaela Wenzel
Pharmaceuticals 2021, 14(5), 392; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050392
Received: 24 March 2021 / Revised: 17 April 2021 / Accepted: 19 April 2021 / Published: 21 April 2021
(This article belongs to the Special Issue Mechanisms of Antibiotic Action and Resistance)
During the last decades, a continuous rise of multi-drug resistant pathogens has threatened antibiotic efficacy. To tackle this key challenge, novel antimicrobial therapies are needed with increased specificity for the site of infection. Photopharmacology could enable such specificity by allowing for the control of antibiotic activity with light, as exemplified by trans/cis-tetra-ortho-chloroazobenzene-trimethoprim (TCAT) conjugates. Resistance development against the on (irradiated, TCATa) and off (thermally adapted, TCATd) states of TCAT were compared to that of trimethoprim (TMP) in Escherichia coli mutant strain CS1562. Genomics and transcriptomics were used to explore the acquired resistance. Although TCAT shows TMP-like dihydrofolate reductase (DHFR) inhibition in vitro, transcriptome analyses show different responses in acquired resistance. Resistance against TCATa (on) relies on the production of exopolysaccharides and overexpression of TolC. While resistance against TCATd (off) follows a slightly different gene expression profile, both indicate hampering the entrance of the molecule into the cell. Conversely, resistance against TMP is based on alterations in cell metabolism towards a more persister-like phenotype, as well as alteration of expression levels of enzymes involved in the folate biosynthesis. This study provides a deeper understanding of the development of new therapeutic strategies and the consequences on resistance development against photopharmacological drugs. View Full-Text
Keywords: photoswitchable antibiotic; trimethoprim; TCAT; resistance mechanism; E. coli; TolC; exopolysaccharides photoswitchable antibiotic; trimethoprim; TCAT; resistance mechanism; E. coli; TolC; exopolysaccharides
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MDPI and ACS Style

Lauxen, A.I.; Kobauri, P.; Wegener, M.; Hansen, M.J.; Galenkamp, N.S.; Maglia, G.; Szymanski, W.; Feringa, B.L.; Kuipers, O.P. Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic. Pharmaceuticals 2021, 14, 392. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050392

AMA Style

Lauxen AI, Kobauri P, Wegener M, Hansen MJ, Galenkamp NS, Maglia G, Szymanski W, Feringa BL, Kuipers OP. Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic. Pharmaceuticals. 2021; 14(5):392. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050392

Chicago/Turabian Style

Lauxen, Anna I., Piermichele Kobauri, Michael Wegener, Mickel J. Hansen, Nicole S. Galenkamp, Giovanni Maglia, Wiktor Szymanski, Ben L. Feringa, and Oscar P. Kuipers 2021. "Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic" Pharmaceuticals 14, no. 5: 392. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050392

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