Protein synthesis inhibitors may be more effective in battling MRSA infections

April 25, 2013 – Vance Fowler, MD, MHS, and other Duke researchers compared the effects of two antibiotics on MRSA-infected rats.

The antibiotic linezolid, a protein synthesis inhibitor, may be superior to the cell wall-active agent vancomycin in treating methicillin-resistant Staphylococcus aureus (MRSA). That is the finding of a new study published in the online journal PLOS One this month.

The study was conducted by the DCRI’s Vance Fowler, MD, MHS, and Duke’s Batu K. Sharma-Kuinkel, PhD, Yurong Zhang, Qin Yan, and Sun Hee Ahn, PhD.

MRSA is a type of bacterium that can cause serious infections and is resistant to certain antibiotics. Recent studies have identified specific bacterial toxins that may be responsible for MRSA infections. These studies have also concluded that protein synthesis inhibitors could be used to interrupt bacterial toxin synthesis by reducing toxin production, thus improving outcomes for patients. Cell wall-active agents, by contrast, either have no effect or enhance the production of extracellular virulence factors. However, the full impact of protein synthesis inhibitors such as linezolid on the host–pathogen interaction in MRSA infections has not been studied until now.

In this study, Fowler and his research team examined the effect of linezolid and vancomycin on both the host and the pathogen. Mice were injected with S aureus USA300 and then intravenously treated with 25 mg/kg of either linezolid or vancomycin. The researchers found that linezolid was more effective than vancomycin at lowering in vivo levels of important staphylococcal toxins such as alpha-hemolysin and Panton-Valentine leukocidin (PVL). These findings, the researchers concluded, provide evidence that protein-synthesis inhibitors such as linezolid that act on a ribosomal level are more effective toxin suppressors than cell wall-active agents such as vancomycin.

The study also revealed differences in host inflammatory response and host gene expression characteristics in MRSA infections. Both agents reduced pro-inflammatory cytokine production in the serum of the infected mice, albeit by different mechanisms. Previous research has indicated that inflammatory cytokines and chemokines play a major role in mediating, amplifying, and perpetuating inflammation in MRSA infections. Taken together, the researchers concluded, these findings suggest that linezolid’s effect on S aureus-infected patients is complex and due at least in part to the bacterium’s effect on both bacterial protein and host cytokine production.

Fowler and his colleagues noted that this study could help unravel the complex relationship between host and pathogen in MRSA infections.