Methods and compositions for the inhibition of quorum sensing in bacterial infections

Principal Investigators: Nicholas Oberlies, Tamam El_Elimat

Application Number: 16/301,426

UNCG Number: 16-0008

Category: Chemistry And Biochemistry

Description:

As the leading cause of infectious mortality in the United States, S. aureus-induced disease represents a major healthcare problem. The alarming rise of infections caused by virulent, antibiotic resistant strains, such as emerging methicillin-resistant S. aureus (MRSA) isolates, highlight the need for new interventions that inhibit MRSA pathogenicity and potentiate host defense responses. The expression of MRSA virulence factors is a function of agr-driven quorum sensing, making this system a promising target for anti-MRSA therapies.

Through agr-reporter-based screens, a class of compounds, called apicidins, were found to inhibit quorum-sensing activity across MRSA isolates. The abatement MRSA virulence in the apicidin-treated group was demonstrated by reduced: weight loss, dermonecrosis and cutaneous bacterial burden. By challenging mice with an agr-reporter strain, we also found that the apicidin-mediated attenuation of MRSA pathogenesis corresponded with reduced quorum sensing activity in vivo.

To evaluate apicidin’s impact upon anti-MRSA effector responses, we assessed polymorphonuclear neutrophil (PMN) accumulation and function at cutaneous sites of infection. Flow cytometric analysis revealed that apicidin increased the density of PMNs within infected wounds 24 hours post infection. In addition, we found that the number of PMNs that phagocytosed MRSA organisms in vivo was increased in lesional skin preparations from apicidin treated mice. Together, these results indicate that apicidin-mediated quorum quenching represents a novel strategy to limit MRSA virulence and promote host defense.

Immediate & Future Applications:
Treating infections. Apicidin should help the host clear an infection. Alternatively, it may be beneficial to mix apicidin with a standard antibiotic (sort of like adding it to ‘neosporin’). Essentially, the experiments that have been performed have examined topical infections.

Inventor Info: Nicholas Oberlies

Inventor Info: Tamam El Elimat

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