The enhancement effect of small molecule Lyb24 reveals AzoR as a novel target of polymyxin B

Hu, Chunxia1,2; Zhang, Jinyong3; Cui, Ruiqin1,2; Liu, Shiyi1,2; Huang, Ying4; Zeng, Huan2,5; Cheng, Shumin1,2; Zhou, Guibao6; Li, Jingli7; Sun, Longqin7; Zhao, Yan7; Wang, Xiao6; Liu, Jianhua3; Zou, Quanming3; Huang, Wei1,2,8

2023-12-31

10.1016/j.biopha.2023.115856

BIOMEDICINE & PHARMACOTHERAPY   影响因子和分区

0753-3322

1950-6007

Given the important role of polymyxin B (PB) in the treatment of drug-resistant Gram-negative bacterial infections, the emergence of PB resistance poses a serious threat to public health. Adjuvant development is a supplementary strategy that can compensate for the lack of novel antibiotics by protecting PB. In this study, we found a small molecule named Lyb24 that showed weak antibacterial activity (minimum inhibitory concentration >= 10 mu g/ml) but potentiated and revitalized the efficacy of PB against Gram-negative pathogens, including mcr-1- and mgrB-deletion-mediated PB-resistant strains. Our results showed that Lyb24 inhibits the translational levels of genes associated with the modification of lipid A. In addition, Lyb24 increases the permeability, disrupts the integrity and induces the depolarization of the membrane. We further found that both Lyb24 and PB could directly bind to AzoR and inhibit its activity. Structural analysis showed that Lyb24 binds to the isoalloxazine ring of flavin mononucleotide (FMN) through pi-pi stacking and loop eta 4 of AzoR. A pneumonia model was used to confirm that the activity against clinical PB-resistant Klebsiella pneumoniae was enhanced due to Lyb24 on PB. In conclusion, we provide a potential therapeutic regimen by combining Lyb24 and PB to treat Gram-negativeresistant bacterial infections. Our findings not only explain the synergistic effect of Lyb24, but also expand our knowledge on the mechanism of action of PB.

Antibiotic adjuvant Drug screening Polymyxin B Susceptibility Gram-negative pathogen

SCI

英语

第一 ; 通讯

Foundation of Guangdong Province[2020B1515120066] ; National Natural Science Foundation of China[82173859]

Research & Experimental Medicine ; Pharmacology & Pharmacy

Medicine, Research & Experimental ; Pharmacology & Pharmacy

WOS:001133554200001

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Web of Science

1.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Affiliated Hosp 1,Clin Med Coll 2,Dept Med Lab, Shenzhen 518020, Guangdong, Peoples R China
2.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1,Clin Med Coll 2,Shenzhen Inst Re, Shenzhen 518020, Guangdong, Peoples R China
3.Third Mil Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China
4.South China Agr Univ, Coll Vet Med, Guangzhou 510642, Guangdong, Peoples R China
5.Jinan Univ, Coll Pharm, Guangzhou 510632, Guangdong, Peoples R China
6.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1,Clin Med Coll 2,Dept Pharm, Shenzhen 518020, Guangdong, Peoples R China
7.Beijing Qinglian Biotech Co Ltd, Beijing 100094, Peoples R China
8.Jinan Univ, Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1,Clin Med Coll 2,Div Hepatobiliar, Shenzhen 518020, Guangdong, Peoples R China

Hu, Chunxia,Zhang, Jinyong,Cui, Ruiqin,et al. The enhancement effect of small molecule Lyb24 reveals AzoR as a novel target of polymyxin B[J]. BIOMEDICINE & PHARMACOTHERAPY,2023,169.

Hu, Chunxia.,Zhang, Jinyong.,Cui, Ruiqin.,Liu, Shiyi.,Huang, Ying.,...&Huang, Wei.(2023).The enhancement effect of small molecule Lyb24 reveals AzoR as a novel target of polymyxin B.BIOMEDICINE & PHARMACOTHERAPY,169.

Hu, Chunxia,et al."The enhancement effect of small molecule Lyb24 reveals AzoR as a novel target of polymyxin B".BIOMEDICINE & PHARMACOTHERAPY 169(2023).