A structure activity relationship study of 3,4'-dimethoxyflavone for ArlRS inhibition in Staphylococcus aureus.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are difficult to treat due to their resistance to many ß-lactam antibiotics, and their highly coordinated excretion of virulence factors. One way in which MRSA accomplishes this is by responding to environmental stimuli using two-component systems (TCS). The ArlRS TCS has been identified as having a key role in regulating virulence in both systemic and local infections caused by S. aureus. We recently disclosed 3,4'-dimethoxyflavone as a selective ArlRS inhibitor. In this study we explore the structure-activity relationship (SAR) of the flavone scaffold for ArlRS inhibition and identify several compounds with increased activity compared to the parent. Additionally, we identify a compound that suppresses oxacillin resistance in MRSA, and begin to probe the mechanism of action behind this activity.

A scaffold hopping strategy to generate new aryl-2-amino pyrimidine MRSA biofilm inhibitors.

Infections that stem from bacterial biofilms are difficult to eradicate. Within a biofilm state, bacteria are upwards of 1000-fold more resistant to conventional antibiotics, necessitating the development of alternative approaches to treat biofilm-based infections. One such approach is the development of small molecule adjuvants that can inhibit/disrupt bacterial biofilms. When such molecules are paired with conventional antibiotics, these dual treatments present a combination approach to eradicate biofilm-based infections. Previously, we have demonstrated that small molecules containing either a 2-amino pyrimidine (2-AP) or a 2-aminoimidazole (2-AI) heterocycle are potent anti-biofilm agents. Herein, we now report a scaffold hopping strategy to generate new aryl 2-AP analogs that inhibit biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA). These molecules also suppress colistin resistance in colistin resistant Klebsiella pneumoniae, lowering the minimum inhibitory concentration (MIC) by 32-fold.