# Mutation of lipoprotein processing pathway gene lspA or inhibition of LspA activity by globomycin increases MRSA resistance to β-lactam antibiotics

## TL;DR

This study shows that disrupting the LspA gene or inhibiting its activity increases resistance to β-lactam antibiotics in MRSA, independent of PBP2a.

## Contribution

The study identifies a novel role for the LspA gene in MRSA β-lactam resistance unrelated to PBP2a or peptidoglycan composition.

## Key findings

- Mutation of the lspA gene increases β-lactam resistance in MRSA independently of PBP2a levels.
- Inhibition of LspA activity by globomycin also enhances β-lactam resistance in MRSA.
- Accumulation of diacylglyceryl-lipoprotein, the LspA substrate, correlates with increased β-lactam resistance.

## Abstract

Resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus is mediated by the mecA-encoded, β-lactam-resistant transpeptidase, penicillin-binding protein 2a (PBP2a), which is capable of crosslinking peptidoglycan in the presence of β-lactam antibiotics. Here, we report that mutation of the lipoprotein signal peptidase II gene, lspA, from the lipoprotein processing pathway, significantly increased β-lactam resistance in MRSA, independent of changes in PBP2a levels or peptidoglycan composition. Exposure of MRSA to the LspA inhibitor globomycin also increased β-lactam resistance. Mutation of lgt, which encodes diacylglycerol transferase (Lgt) responsible for synthesis of the LspA substrate, did not impact β-lactam susceptibility. Furthermore, mutation of lgt in an lspA background restored β-lactam resistance to wild-type levels. These data suggest that accumulation of the LspA substrate, diacylglyceryl-lipoprotein, is associated with increased β-lactam resistance in MRSA.