Betulinic Acid Prevents the Acquisition of Ciprofloxacin-Mediated Mutagenesis in .

The occurrence of damage on bacterial DNA (mediated by antibiotics, for example) is intimately associated with the activation of the SOS system. This pathway is related to the development of mutations that might result in the acquisition and spread of resistance and virulence factors. The inhibition of the SOS response has been highlighted as an emerging resource, in order to reduce the emergence of drug resistance and tolerance. Herein, we evaluated the ability of betulinic acid (BA), a plant-derived triterpenoid, to reduce the activation of the SOS response and its associated phenotypic alterations, induced by ciprofloxacin in . BA did not show antimicrobial activity against (MIC > 5000 µg/mL), however, it (at 100 and 200 µg/mL) was able to reduce the expression of induced by ciprofloxacin. This effect was accompanied by an enhancement of the ciprofloxacin antimicrobial action and reduction of cell volume (as seen by flow cytometry and fluorescence microscopy). BA could also increase the hyperpolarization of the membrane, related to the ciprofloxacin action. Furthermore, BA inhibited the progress of tolerance and the mutagenesis induced by this drug. Taken together, these findings indicate that the betulinic acid is a promising lead molecule in the development helper drugs. These compounds may be able to reduce the mutagenicity associated with antibiotic therapies.