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

Huang，Wei1,2; Zhang，Jinyong3; He，Yuzhang4; Hu，Chunxia1; Cheng，Shumin1; Zeng，Huan5; Zheng，Manling6; Yu，Huijuan1,2; Liu，Xue4; Zou，Quanming3; Cui，Ruiqin1

2022-09-06

10.3389/fphar.2022.949869

Frontiers in Pharmacology   Impact Factor & Quartile

1663-9812

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.

antibiotic adjuvant Klebsiella pneumoniae lipid A lipopolysaccharide polymyxin B resistant two-component system

SCI

English

First ; Corresponding

Shenzhen Key Laboratory of Prevention and Treatment of Severe Infections( China)[SZXK059] ; Guangdong Basic and Applied Basic Research Foundation (China)[ZDSYS20200811142804014] ; National Nature Science Foundation of China( China)[2020B1515120066] ; [82173859]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000857876200001

FRONTIERS MEDIA SA

2-s2.0-85138291166

Scopus

1.Antimicrobial Drug Screening Laboratory,Shenzhen Institute of Respiratory Diseases,Shenzhen People’s Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,China
2.Department of Clinical Microbiology,Shenzhen People’s Hospital,The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,China
3.National Engineering Research Center of Immunological Products,Department of Microbiology and Biochemical Pharmacy,College of Pharmacy,Third Military Medical University,Chongqing,China
4.Department of Pathogen Biology,International Cancer Center,Shenzhen University Health Science Center,Shenzhen,China
5.College of Pharmacy,Jinan University,Guangzhou,China
6.Medical College,Shantou University,Shantou,China

Huang，Wei,Zhang，Jinyong,He，Yuzhang,et al. A cyclic adenosine monophosphate response element-binding protein inhibitor enhances the antibacterial activity of polymyxin B by inhibiting the ATP hydrolyzation activity of CrrB[J]. Frontiers in Pharmacology,2022,13.

Huang，Wei.,Zhang，Jinyong.,He，Yuzhang.,Hu，Chunxia.,Cheng，Shumin.,...&Cui，Ruiqin.(2022).A cyclic adenosine monophosphate response element-binding protein inhibitor enhances the antibacterial activity of polymyxin B by inhibiting the ATP hydrolyzation activity of CrrB.Frontiers in Pharmacology,13.

Huang，Wei,et al."A cyclic adenosine monophosphate response element-binding protein inhibitor enhances the antibacterial activity of polymyxin B by inhibiting the ATP hydrolyzation activity of CrrB".Frontiers in Pharmacology 13(2022).