Native graS mutation supports the susceptibility of Staphylococcus aureus strain SG511 to antimicrobial peptides

Staphylococcus aureus strain SG511-Berlin has been used as a standard strain for antimicrobial susceptibility testing and basic research since the first half of the last century. This study aimed at the identification of features of S. aureus SG511-Berlin that contribute to its high susceptibility to antimicrobial peptides (AMPs) in order to give insights into the mechanisms that S. aureus uses to counteract antimicrobials and to evaluate the role of S. aureus SG511-Berlin as a standard test strain. Comparative transcriptional profiling of S. aureus SG511-Berlin versus the more resistant S. aureus SA137/93A revealed a divergent regulation of the dltB, mprF, and vraFG genes, which are under the control of the two-component regulatory system (TCRS) GraRS. These gene transcripts showed significantly lower abundance in strain SG511-Berlin. Sequence analysis of graS in strain SG511-Berlin revealed a native nucleotide insertion that generates a stop codon at position 64 of the sensor histidine kinase GraS, thereby deleting the entire cytoplasmic part of the protein. Quantitative RT-PCR and determination of the whole-cell surface charge of graS complemented S. aureus SG511-Berlin directly linked its decreased dltB transcript level and the resulting increased negative cell surface charge to the nucleotide insertion in graS. Further MIC testings identified the GraRS TCRS as a resistance determinant to the lantibiotics mersacidin, nisin, and Pep5. Due to these findings, the use of S. aureus SG511-Berlin for research purposes should be carefully considered, since this strain does not reflect the normal response of S. aureus against antibiotics.