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.

Automated summary

Infections stemming from bacterial biofilms are difficult to eradicate, requiring the development of alternative treatment approaches. Pairing small molecule adjuvants with conventional antibiotics can effectively treat these infections. New aryl 2-AP analogs generated through a scaffold hopping strategy show potential in inhibiting biofilm formation and resistance in bacteria.