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

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.

SUBMITTER: Lauxen AI

PROVIDER: S-EPMC8143356 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Adaptive antibiotic resistance is a transient metabolic adaptation of bacteria limiting their sensitivity to low, progressively increased, concentrations of antibiotics. Unlike innate and acquired resistance, adaptive resistance is dependent on the presence of antibiotics, and it disappears when the triggering factor is removed. Low concentrations of antibiotics are largely diffused in natural environments, in the food industry or in certain body compartments of humans when used therapeutically, or in animals when used for growth promotion. However, molecular mechanisms underlying this phenomenon are still poorly characterized. Here, we present experiments suggesting that epigenetic modifications, triggered by low concentrations of ampicillin, gentamicin, and ciprofloxacin, may modulate the sensitivity of bacteria to antibiotics. The epigenetic modifications we observed were paralleled by modifications of the expression pattern of many genes, including some of those that have been found mutated in strains with permanent antibiotic resistance. As the use of low concentrations of antibiotics is spreading in different contexts, our findings may suggest new targets and strategies to avoid adaptive antibiotic resistance. This might be very important as, in the long run, this transient adaptation may increase the chance, allowing the survival and the flourishing of bacteria populations, of the onset of mutations leading to stable resistance. IMPORTANCE In this study, we characterized the modifications of epigenetic marks and of the whole transcriptome in the adaptive response of Escherichia coli cells to low concentrations of ampicillin, gentamicin, and ciprofloxacin. As the transient adaptation does increase the chance of permanent resistance, possibly allowing the survival and flourishing of bacteria populations where casual mutations providing resistance may give an immediate advantage, the importance of this study is not only in the identification of possible molecular mechanisms underlying adaptive resistance to antibiotics, but also in suggesting new strategies to avoid adaptation.

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

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