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Bacterial resistance to β-lactams may rely on acquired β-lactamases encoded by class 1 integron-borne genes. Rearrangement of integron cassette arrays is mediated by the integrase IntI1. It has been previously established that integrase expression can be activated by the SOS response in vitro, leading to speculation that this is an important clinical mechanism of acquiring resistance. Here we report the first in vivo evidence of the impact of SOS response activated by the antibiotic treatment given to a patient and its output in terms of resistance development. We identified a new mechanism of modulation of antibiotic resistance in integrons, based on the insertion of a genetic element, the gcuF1 cassette, upstream of the integron-borne cassette bla OXA-28 encoding an extended spectrum β-lactamase. This insertion creates the fused protein GCUF1-OXA-28 and modulates the transcription, the translation, and the secretion of the β-lactamase in a Pseudomonas aeruginosa isolate (S-Pae) susceptible to the third generation cephalosporin ceftazidime. We found that the metronidazole, not an anti-pseudomonal antibiotic given to the first patient infected with S-Pae, triggered the SOS response that subsequently activated the integrase IntI1 expression. This resulted in the rearrangement of the integron gene cassette array, through excision of the gcuF1 cassette, and the full expression the β-lactamase in an isolate (R-Pae) highly resistant to ceftazidime, which further spread to other patients within our hospital. Our results demonstrate that in human hosts, the antibiotic-induced SOS response in pathogens could play a pivotal role in adaptation process of the bacteria., Author Summary The bacterial SOS response is a conserved regulatory network that is induced in response to DNA damage. Its activation in vitro leads to the emergence of resistance to antibiotics, leading to speculation that this is an important clinical mechanism of acquiring resistance. We found evidence here that antibiotic-induced SOS response plays a role in bacterial genome rearrangement in vivo within humans. The major classes of antibiotics can trigger the bacterial SOS response and our data raise questions about their wide use and their subsequent effect on the bacterial genetic adaptability. This suggests that emergence of antibiotic resistance during therapy could be reduced by inhibiting the bacterial SOS response. We showed that acquired resistance genes could spread latently in susceptible bacterial strains until needed. These findings could impact current policies for control of antibiotic resistance, which rely on the detection of resistant bacteria and on the assumption that resistance mechanisms have a functional cost to the bacteria. More generally, SOS response may spur changes in the behavior of bacteria and their faster adaptation to hostile environments, including humans.

Emilie Guerin, Guillaume Cambray, Sandra Da Re, Didier Mazel, Marie-Cecile Ploy E. Guerin, S. Da Re : Universite de Limoges, EA3175 ; Inserm, equipe Avenir Inserm, faculte de medecine, Limoges, France. G. Cambray, D. Mazel : Institut Pasteur, unite Plasticite du genome bacterien, Paris, 28, rue du Docteur Roux, 75015 Paris, France. M.C. Ploy : Universite de Limoges, EA3175, Equipe Avenir Inserm, Limoges, France. marie-cecile.ploy@unilim.fr NOUVELLE

We describe the first IMP metallo-β-lactamase in Aeromonas caviae : IMP-19, which differed from IMP-2 by a single amino acid change (Arg to Ala at position 38). bla IMP-19 was found within a class 1 integron located on a 35-kb plasmid. This is also the first description of an IMP producer in France.