YgfB increases β-lactam resistance inPseudomonas aeruginosaby counteracting AlpA-mediatedampDh3expression

AbstractYgfB-mediated β-lactam resistance was recently identified in multi drug resistantPseudomonas aeruginosa. Weshow that YgfB upregulates expression of the β-lactamase AmpC by repressing the function of the regulator of the programmed cell death pathway AlpA. In response to DNA damage, the antiterminator AlpA induces expression of thealpBCDEautolysis genes and of the peptidoglycan amidase AmpDh3. YgfB interacts with AlpA and represses theampDh3expression.Thus, YgfB indirectly prevents AmpDh3 from reducing the levels of cell wall-derived 1,6-anhydro-N-acetylmuramyl-peptides, required to induce the transcriptional activator AmpR in promoting theampCexpression and β-lactam resistance. Ciprofloxacin-mediated DNA damage induces AlpA-dependent production of AmpDh3 as previously shown, which should reduce β-lactam resistance. YgfB, however, counteracts the β-lactam enhancing activity of ciprofloxacin by repressingampDh3expression and lowering the benefits of this drug combination.Altogether, YgfB represents a new player in the complex regulatory network of AmpC regulation.