The Proteus mirabilis PmirS clinical isolate, which was susceptible to imipenem (0.5 μg/mL) and amikacin (1 μg/mL), was recovered from a bronchial aspirate of a patient who recently underwent lung transplantation. The P. mirabilis PmirR clinical isolate, which exhibited resistance to imipenem (16 μg/mL) and amikacin (24 μg/mL), was isolated 3 weeks later from the same patient and the same specimen type. Using short-read sequencing technology, these isolates appeared to be genetically identical except the cpxA gene of the PmirR isolate that was mutated leading to the His-208-Pro substitution. The structural alteration was localized in the histidine kinase, adenylate cyclase, methyl accepting protein, phosphatase (HAMP) domain, which is involved in the signal transduction between the sensor kinase and the regulator response of the CpxA/CpxR two-component system (TCS). No significant defect in the growth rate was found between the PmirS and PmirR isolates. This study suggests that alteration in CpxA might confer imipenem and amikacin resistance in P. mirabilis. This study brings new evidence that the TCS alteration could provide an adaptive capacity in a clinical context by conferring antibiotic resistance without fitness cost.