Mutations in Genes Encoding Penicillin-Binding Proteins and Efflux Pumps Play a Role in β-Lactam Resistance in Helicobacter Cinaedi

β-Lactams are often used to treat infections; however, the mechanism underlying β-lactam resistance is unknown. In this study, we investigated β-lactam resistance in an strain, MRY12-0051 (MICs of amoxicillin [AMX] and ceftriaxone [CRO], 32 and 128 μg/ml; obtained from human feces). Based on a comparative whole-genome analysis of MRY12-0051 and the CRO-susceptible strain MRY08-1234 (MICs of AMX and CRO, 1 and 4 μg/ml; obtained from human blood), we identified five mutations in genes encoding penicillin-binding proteins (PBPs), including two in , one in , and two in Transformation and penicillin binding assays indicated that CRO resistance was mainly associated with mutations in ; mutations in also led to increased resistance to AMX. Knocking out and , which encode resistance-nodulation-division-type efflux pump components, in type strain CCUG18818 (AMX MIC, 4 to 8 μg/ml) resulted in 8- and 64-fold decreases, respectively, in the AMX MIC. Hence, MICs of AMX in become similar to those of isolates in the absence of In conclusion, the difference in susceptibility to β-lactams between and is explained by differences in efflux pump components. Mutations in are the primary determinant of high resistance to β-lactams in .