A pbpB1 mutation causing β-lactam resistance in clinical Listeria monocytogenes isolates

Objectives: Listeriosis is a severe foodborne infection and associated with high mortality. Treatment is based on ampicillin, amoxicillin or penicillin, often combined with gentamicin, but meropenem is also used occasionally. β-lactam resistant Listeria monocytogenes isolates are infrequently described but the mechanism of resistance is not known. Methods: A clinical L. monocytogenes isolate with suspected β-lactam resistance was collected from a German listeriosis patient. Resistance profiling, whole genome sequencing, comparative genomics and genetic experiments were used to identify the causative DNA polymorphism. Spontaneous ampicillin resistant suppressors of L. monocytogenes reference strain EGD-e were selected and their genomes sequenced. Results: A W428R substitution near the active site of penicillin binding protein B1 (PBP B1) was identified as the cause of ampicillin, amoxicillin and meropenem resistance. Further clinical L. monocytogenes isolates with similar resistance profiles were found by searching the genome database of the German consultant laboratory for Listeria for pbpB1 W428R-positive isolates. Furthermore, the same mutation was selected for in strain EGD-e during cultivation in the presence of ampicillin. Conclusions: L. monocytogenes can develop β-lactam resistance by a specific substitution in PBP B1, likely selected for during β-lactam treatment. Antibiotic susceptibility testing should be considered an important part of adequate listeriosis therapy.