Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae

AMB Express

Thiagarajan Raman¹  Niranjana Sri Sundaramoorthy²  Saisubramanian Nagarajan²  Harihar M. Mohan³  Subramaniapillai Selva Ganesan⁴  Aravind Sivasubamanian⁴  Shankar Subramaniam⁴ 

[1] Advanced Zoology and Biotechnology Department, Ramakrishna Mission Vivekananda College;Center for Research on Infectious Diseases, SCBT, SASTRA Deemed University;Department of Microbiology and Immunology, University of Michigan Medical School;School of Chemical and Biotechnology, SASTRA Deemed University;

关键词: Synergy;    Ursolic acid;    Colistin resistance;    Klebsiella pneumoniae;    E. coli;    Zebrafish infection;   

DOI  :  10.1186/s13568-019-0750-4

来源: DOAJ

【 摘 要 】

Abstract Colistin resistance in Enterobacteriaceae especially Klebsiella pneumoniae and Escherichia coli is driving the evolution of pan drug resistant strains. Screening a library of 13 plant nutraceuticals led to the identification of acetyl shikonin and ursolic acid, which exhibited synergy with colistin against extremely drug resistant (XDR) clinical strains of E. coli (U3790) and K. pneumoniae (BC936). Ursolic acid caused a significant colistin MIC reversal of 16-fold in U3790 and 4-fold in BC936 strains. Ursolic acid also potentiated the bactericidal effect of colistin against both U3790 and BC936 by causing ~ 4 to 4.5 log fold decline in CFU of both clinical isolates in a time kill assay. At 2× minimum effective concentration, ursolic acid was non-toxic to zebrafish as evidenced by brain and liver enzyme profiles and by histopathology studies. In combination with colistin, ursolic acid reduced bacterial bioburden of U3790/BC936 by 1–1.58 log fold from the infected muscle tissue of zebrafish. Mechanistic explorations via studies on real time efflux, membrane potential and intracellular accumulation of dansyl chloride tagged colistin revealed that colistin efflux is inhibited by ursolic acid. In addition, ursolic acid also enhanced outer membrane permeability which probably facilitates colistin’s attack on outer and inner membranes. Our study shows that ursolic acid synergizes with colistin by inhibiting colistin efflux in Enterobacteriaceae that helps to curtail colistin resistant Enterobacteriaceae.

【 授权许可】

Unknown