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

Abstract

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 Klebsiella pneumoniae in vitro and in vivo. 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.

Dronedarone Enhances the Antibacterial Activity of Polymyxin B and Inhibits the Quorum Sensing System by Interacting with LuxS

“…Dronedarone blocks potassium, sodium, and L-type calcium currents and exerts antiadrenergic effects by noncompetitive binding to β-adrenergic receptors . However, when nonantibiotic drugs are used as antibiotic potentiators, their mechanisms of action are usually different from their original pharmacological effects. − The ability of β-adrenoreceptor antagonists or blockers to inhibit the QS system has been demonstrated by previous studies. ,, However, the target of QS suppression was not been identified.…”

“…Survival rate, lung bacterial load, and histopathology analyses were performed as previously described. 30 All animal experiments in this study were approved by the Animal Ethical and Experimental Committee of the Army Military Medical University (approval no.…”

“…Saline, dronedarone (10 mg/kg), PB (0.2 mg/kg) alone, or a combination of PB (0.2 mg/kg) and dronedarone (1, 5, and 10 mg/kg) was injected intraperitoneally into mice 2 h after infection. Survival rate, lung bacterial load, and histopathology analyses were performed as previously described . All animal experiments in this study were approved by the Animal Ethical and Experimental Committee of the Army Military Medical University (approval no.…”