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

Abstract

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.