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

Anna I Lauxen, Piermichele Kobauri, Michael Wegener, Mickel J Hansen, Nicole S Galenkamp, Giovanni Maglia, Wiktor Szymanski, Ben L Feringa*, Oscar P Kuipers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article numberph14050392
Number of pages18
JournalPharmaceuticals
Volume14
Issue number5
DOIs
Publication statusPublished - 21-Apr-2021

Keywords

  • photoswitchable antibiotic
  • trimethoprim
  • TCAT
  • resistance mechanism
  • E. coli
  • TolC
  • exopolysaccharides

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