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Targeting the Virulence Factors of MRSA

Amesh A. Adalja, MD, FACP, FACEP, FIDSA, December 2, 2016

Despite the availability of highly effective therapies directed against methicillin-resistant Staphylococcus aureus (MRSA), it still exacts a considerable toll of morbidity and mortality. In its 2013 report, the CDC labeled MRSA a serious threat and estimated that it causes more than 11,000 deaths annually.1 Because of this sizable impact, there is a pressing need to improve therapy for MRSA infections beyond the various antibiotics that are predictably active against it. A new paper published in the Journal of Infectious Diseases describes a potential avenue to improve outcomes in MRSA infections.2

 

β-lactam Antibiotics: Pleiotropic Effects

By definition, MRSA is resistant to all available β-lactam class antibiotics (except ceftaroline); however, antibiotics have additional properties beyond their antibiotic activity, such as interfering with bacterial virulence factors. To explore this possibility, Waters and colleagues performed a series of experiments in mice and on cells.

In mouse MRSA sepsis models, Waters and colleagues administered the β-lactam antibiotic oxacillin at varying doses  and found that both therapeutic and subtherapeutic dosages reduced bacterial burdens in both the spleen and kidney. Similar results were seen in a pneumonia model as well.

Studies with human neutrophils showed diminished susceptibility to the MRSA Panton-Valentine (PVL) toxin in the presence of oxacillin in certain culture media and, importantly, showed diminished toxicity of supernatants from highly virulent Agr mutants. Agr mutants are known to produce more toxins, and it appears that oxacillin down-regulated the effects of Agr. Additionally, it was shown that oxacillin could increase the incorporation of techoic acid in the cell wall of MRSA, enhancing its susceptibility to the complement component of the immune system.

 

Virulence Factor Disruption as a Therapeutic Strategy

The work of Waters and colleagues provides evidence of the feasibility of approaching the challenges of antibiotic resistance not only by developing new antibacterial compounds but also through attacking the virulence factors that are responsible for the damage these pathogens induce. While these animal and in vitro studies will need to be further explored and are “hypothesis generating,” as the accompanying editorial by Bayer and Xiong notes,3 there is already some evidence—from a randomized controlled trial—that such an approach may be beneficial in treating human infections.4

As antibiotic resistance continues to remain a top public health threat, exploring all options—including attenuating virulence factors—will be a priority.

 

References

  1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed November 29, 2016.
  2. Waters EM, Rudkin JK, Coughlan S, et al. Redeploying β-lactam antibiotics as a novel antivirulence strategy for the treatment of methicillin-resistant Staphylococcus aureus infections. J Infect Dis 2016; http://jid.oxfordjournals.org/content/early/2016/11/10/infdis.jiw461.abstract. Accessed November 29, 2016.
  3. Bayer AS, Xiong YQ. Redeploying β-lactams against Staphylococcus aureus: repurposing with a purpose. J Infect Dis 2016; http://jid.oxfordjournals.org/content/early/2016/11/10/infdis.jiw464.full. Accessed November 29, 2016.
  4. Davis JS, Sud A, O'Sullivan MV, et al. Combination of vancomycin and β-lactam therapy for methicillin-resistant Staphylococcus aureus bacteremia: a pilot multicenter randomized controlled trial. Clin Infect Dis 2016;62(2):173-180.