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Abstract
In addition to discovering new antibiotics to combat antibiotic resistance, there is a critical need to develop novel strategies that could limit off-target effects and unnecessary exposure of antibiotics to bacteria in our body and environment, respectively. We report a set of novel, photoswitchable arylazopyrazole-modified norfloxacin antibiotics that presents a high degree of bidirectional photoisomerization, impressive fatigue resistance, and reasonably high cis half-lives, and exhibits antibacterial activity selectively against Gram-positive bacteria; the cis isomers of most compounds were found to have near equal or greater potency than the norfloxacin, rendering them bactericidal. Remarkably, a visible-light-responsive p-SMe-substituted derivative against the norfloxacin-resistant S. aureus bacteria showed extremely high antimicrobial activity with a MIC of 0.25 ug/mL in the irradiated state and a 24-fold potency difference between irradiated and non-irradiated states. The antimicrobial activity of the irradiated state can be retained for more than 7 hours. The cell-killing ability of this compound was further visualized by Live/Dead cell staining assay and FACS studies. Theoretical calculation and molecular docking studies were performed to identify the underlying reason behind the high-affinity binding of the irradiated form to the topoisomerase IV.
Supplementary materials
Title
Optochemical control of the growth of antibiotic-resistant bacteria using arylazopyrazole-modified norfloxacin
Description
Compounds were purified by column chromatography using silica gel with a mesh size of 100–200. Rotary evaporators were used to evaporate the solvent, and high vacuum pump was then used to dry the products. 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 300 (300 MHz) and Bruker Avance Neo HD 400 (400 MHz) spectrometer. Chemical shifts (δ) are described in parts per million (ppm) and are referenced to the residual signal of the respective NMR solvent. Coupling constants (J) are given in Hz as detected and multiplicity is reported as s (singlet), d (doublet), t (triplet), q (quartet), or m (multiplet). High-resolution mass spectra were collected by the Department of Chemistry Mass Spectroscopy Service using ESI-MS (waters).
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