Branched Polyethylenimine Exposure Changes Phenotypes in Methicillin-Resistant Staphylococcus aureus

Branched polyethylenimine (BPEI) has antibacterial and antibiofilm properties. The utility of this broad-spectrum agent could be hampered if resistance to BPEI develops in bacterial pathogens. In contrast to the paradigm of drug resistance hindering drug development, the emergence of BPEI resistance in Staphylococcus aureus is accompanied by changes in the S. aureus phenotypes that increase susceptibility to β-lactam antibiotics and phagocytic killing. Exposure to BPEI through serial passage leads to resistance in methicillin-resistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) of 600 Da BPEI in the wild-type USA300 MRSA strain is 16 µg/ml while, after 15 serial passages, the MIC increased to 1024 µg/mL. An additional 15 rounds of serial passage in the absence of BPEI did not change the 1024 µg/mL MIC. The resistant MRSA strains show an 8-fold increased susceptibility to oxacillin antibiotic, has a reduced export of acid species and staphyloxanthin pigment, and renders MRSA more susceptible to phagocytic killing by THP-1 monocytes. Whole genome screening data revealed a missense mutation in the vraG gene for both the BPEI resistant USA300 and MW2 strains. This gene is involved with efflux pumps expression and recognition of cationic antimicrobial peptides; thus an altered gene produce may alter export phenotypes and the binding of cationic BPEI to the bacterial cell envelope in line with observations reported in this work.