Methicillin-resistant Staphylococcus aureus (MRSA) is a critical human pathogen and a threat to human health. The β-lactam antibiotic methicillin targets bacterial penicillin-binding proteins (PBPs), which mediate the synthesis of peptidoglycan in the cell wall during cell growth and division. MRSA has acquired the mecA gene, which encodes penicillin-binding protein 2a (PBP2a). This enzyme replaces the transpeptidase activity of endogenous PBP2 and has a low affinity for β-lactams, leading to resistance to this class of antibiotics. Notably, clinical MRSA isolates exhibit heterogeneous resistance; that is, the population comprises cells that have low, moderate or high levels of antibiotic resistance. The acquisition of mecA results in low-level resistance, and exposure to an antibiotic has been suggested to induce the development of a homogeneous population with a high level of resistance. This conversion has been shown to be linked to mutations in chromosomal genes that encode potentiator (Pot) factors, including genes that encode proteins involved in nucleotide signalling and subunits of RNA polymerase (encoded by rpoB or rpoC). In a new study, Adedeji-Olulana et al. show that high-level resistance in MRSA involves an alternative mode of cell division.

Further experiments revealed that PBP1 is responsible for the formation of the concentric rings of septal peptidoglycan, and in the presence of the antibiotic, this activity of PBP1 is inhibited by the drug. The authors went on to show that PBP2a cannot compensate for the lack of PBP1 activity. By contrast, the rpoB mutations could restore the ability of the bacteria to grow and permitted successful cell division without septal peptidoglycan rings. This led the authors to propose that MRSA with high-level resistance can adopt an alternative mode of division that does not require the septal rings.