Synergistic effect of polymyxin B with baicalein against mcr-1 postive Escherichia coli

Abstract

The frequent emergence of multi-drug resistance Escherichia coli (E. coli) in both poultry and human health has facilitated the demand of seeking a novel therapeutic alternative. Traditional Chinese medicine has become a recent hotspot in drug development due to its efficacious assistance with existing antibiotics against drug-resistant pathogens. Herein, we estimated the synergistic effect of polymyxin B and baicalein (the major integrant of a Chinese herb, Scutellaria baicalensis) against mcr-1 positive E. coli HP144 through checkerboard assays accompanying the time-killing curve, and found that baicalein significantly amplified antimicrobial activity of polymyxin B. E. coli treated with polymyxin B and baicalein also showed an obviously enhanced destruction of bacterial outer membranes through scanning electron microscopy. Furthermore, transcriptome and metabolome analysis were implemented to reveal the molecular mechanism. Various differentially expressed genes were identified between polymyxin B and the drug combined group, especially lipopolysaccharide (LPS) core synthesis genes (rfaQ, rfbB and rfaP) and efflux pump correlative genes (evgA, arcA and mgrB). Metabolome results also illustrated significant alterations of multiple metabolites, including nicotinamide adenine dinucleotide (NAD+) and D-Alanyl-Dalanine dipeptide, which are closely associated with bacterial invasion and outer membrane integrity. Subsequently, mice infection models were utilized to discuss the efficacy of synergistic therapy in vivo. After the co-treatment of polymyxin B and baicalein, bacteria loads in mice abdomens were significantly diminished and the survival rate was remarkably increased by ameliorating inflammatory reactions in mice. In conclusion, by increasing the antibiotic permeability of outer membranes, baicalein could efficiently improve the bactericidal effects of polymyxin B in vitro and in vivo, demonstrating its promising potential as a polymyxin B adjuvant and antibiotic alternative.