Blocking toxin formation – a treatment for Gram-positive pathogens?

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A new study has demonstrated the promise of molecules blocking bacterial toxin formation to treat drug-resistant infections, as MRSA-infected mice all survived when given this small molecule.

With increasing drug-resistance, antivirulence inhibitors are increasingly being viewed as a good alternative to antibiotics. This study, published recently in Scientific Reports, assessed a non-antibiotic strategy for treating methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive infections.

The team assessed two molecules, F12 and F19, which attach to a toxin-producing protein, termed AgrA, across Gram-positive species rendering it ineffective. The team treated MRSA-infected mice with these molecules, demonstrating that it could effectively cure infections; the treated mice had a 100% survival rate, compared with just 30% in the untreated group.

Author, Menachem Shoham (Case Western Reserve University, OH, USA), commented: “Without the toxins the bacteria become harmless. And since they don’t need the toxins to survive, there is less pressure to develop resistance.”

The researchers noted that while F12 is more efficacious in vitro, F19 works better in vivo. Moreover, F19 appeared to reduce bacterial load when combined with antibiotics, suggesting it could be used alone or in combination.

Shoham explained: “For relatively healthy patients, such as athletes suffering from a MRSA infection, these molecules may be enough to clear an infection. For immunocompromised patients, combination therapy with the molecules and a low-dose antibiotic may be in order. The antibiotic in the combination could be one to which the bacteria are resistant in monotherapy, because our small molecules enhance the activity of conventional antibiotics, such as penicillin.”

The study also included preliminary experiments demonstrating F12 and F19 may be effective on other Gram-positive pathogens, as Shoham noted: “We have proven efficacy not only against MRSA but also against Staphylococcus epidermidis, which is notorious for clogging catheters, Streptococcus pyogenes that causes strep throat, Streptococcus pneumoniae, and other pathogens.”

The team is now working to commercialize both drugs. In addition, Case Western Reserve University has issued a license to Q2Pharma (Haifa, Israel) to perform additional preclinical studies and develop both molecules for clinical trials.

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Sources: Greenberg M, Kuo D, Jankowsky E et al. Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens. Sci. Rep. 8, 14578 (2018); http://casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=1513&news_category=8

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