Evidence for Induction of Integron-Based Antibiotic Resistance by the SOS Response in a Clinical Setting

<div><p>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 <em>in vitro</em>, leading to speculation that this is an important clinical mechanism of acquiring resistance. Here we report the first <em>in vivo</em> 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 <em>gcuF1</em> cassette, upstream of the integron-borne cassette <em>bla</em>_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 <em>Pseudomonas aeruginosa</em> isolate (S-<em>Pae</em>) 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-<em>Pae</em>, 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 <em>gcuF1</em> cassette, and the full expression the β-lactamase in an isolate (R-<em>Pae</em>) 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.</p>