A cyclic adenosine monophosphate response element-binding protein inhibitor enhances the antibacterial activity of polymyxin B by inhibiting the ATP hydrolyzation activity of CrrB.

The emergence of polymyxin B (PB) resistant Gram-negative bacteria poses an important clinical and public health threat. Antibiotic adjuvants development is a complementary strategy that fills the gap in new antibiotics. Here, we described the discovery of the enhancement capacity of compound 666-15, previously identified as an inhibitor of cyclic adenosine monophosphate response element-binding protein (CREB), on the activity of PB against and . Mechanistic studies showed that this compound reduced the transcription and translation levels of genes related to lipid A modification in the presence of PB. We also identified that 666-15 reduces the ATP hydrolyzation activity of CrrB, and P151L mutation mediates the resistance of bacteria to the enhancement of 666-15. Our results demonstrated the potential of 666-15 in clinical application and support the further development of a PB synergist based on this compound.