ena-PROJECT-INRA-12-04-2013-13:57:56:610-59
The SOS response controls intrinsic resistance to cephalosporins
Bacterial resistance to antibiotics can be acquired by horizontal gene transfer and mutations or intrinsic due to innate abilities of the bacteria to resist antibiotic pressure. As the intrinsic resistance is considered to be a natural characteristic of a given bacterial species or genus, this obligates to dismiss concerned antibiotics from the therapeutic options of bacterial diseases. Enterococcus faecalis is a major nosocomial pathogen and is intrinsically resistant to cephalosporin family, one of the most used and efficient antimicrobials. Moreover, treatment with cephalosporins to cure other bacterial diseases has been shown to be an important risk factor for development of clinical infections involving E. faecalis. We present here a molecular mechanism through which the intrinsic resistance of E. faecalis to cephalosporins can be abolished such that the bacteria become susceptible. Induction of a DNA-damaged survival mechanism, the so-called SOS response, in wild-type E. faecalis in vitro and in mice infection model in vivo allowed cephalosporins to kill the bacteria. We also show that other bacterial pathogens that are intrinsically resistant to cephalosporins, in particular Listeria ivanovii, similarly become susceptible upon induction of the SOS response. Anaerobic studies showed that this phenomenon was reactive oxygen species-independent. Transcriptomic analyses revealed that the SOS response can modulate indirectly the expression of several genes known to be involved in the cephalosporin intrinsic resistance, such as croS and ireK, but not the expression of pbp5, the main factor implicated in the cephalosporin resistance of Enterococcus. Finally, sequencing of E. faecalis JH2-2 genome discarded the implication of some phages. These findings show that intrinsic antibiotic resistance is regulated by the SOS response, and that it can be reverted to full susceptibility in vitro and in vivo. Further, our results stimulate novel therapeutic options for the treatment of bacterial infections developing novel molecules that reverse intrinsic resistance.
Bacterial resistance to antibiotics can be acquired by horizontal gene transfer and mutations or intrinsic due to innate abilities of the bacteria to resist antibiotic pressure. As the intrinsic resistance is considered to be a natural characteristic of a given bacterial species or genus, this obligates to dismiss concerned antibiotics from the therapeutic options of bacterial diseases. Enterococcus faecalis is a major nosocomial pathogen and is intrinsically resistant to cephalosporin family, one of the most used and efficient antimicrobials. Moreover, treatment with cephalosporins to cure other bacterial diseases has been shown to be an important risk factor for development of clinical infections involving E. faecalis. We present here a molecular mechanism through which the intrinsic resistance of E. faecalis to cephalosporins can be abolished such that the bacteria become susceptible. Induction of a DNA-damaged survival mechanism, the so-called SOS response, in wild-type E. faecalis in vitro and in mice infection model in vivo allowed cephalosporins to kill the bacteria. We also show that other bacterial pathogens that are intrinsically resistant to cephalosporins, in particular Listeria ivanovii, similarly become susceptible upon induction of the SOS response. Anaerobic studies showed that this phenomenon was reactive oxygen species-independent. Transcriptomic analyses revealed that the SOS response can modulate indirectly the expression of several genes known to be involved in the cephalosporin intrinsic resistance, such as croS and ireK, but not the expression of pbp5, the main factor implicated in the cephalosporin resistance of Enterococcus. Finally, sequencing of E. faecalis JH2-2 genome discarded the implication of some phages. These findings show that intrinsic antibiotic resistance is regulated by the SOS response, and that it can be reverted to full susceptibility in vitro and in vivo. Further, our results stimulate novel therapeutic options for the treatment of bacterial infections developing novel molecules that reverse intrinsic resistance.