RESUMEN
The emergence of TMexCD1-TOprJ1, a novel transferable resistance-nodulation-division (RND)-type efflux pump conferring resistance to tigecycline, is now a serious public health issue in the world. Here, we found that melatonin synergistically enhanced the antibacterial efficacy of tigecycline against tmexCD1-toprJ1-positive Klebsiella pneumoniae by disrupting the proton driving force and efflux function to promote the accumulation of tigecycline into cells, damaging cell membrane integrity and causing the leakage of cell contents. The synergistic effect was further validated by a murine thigh infection model. The results revealed that the melatonin/tigecycline combination is a potential therapy to combat resistant bacteria carrying the tmexCD1-toprJ1 gene.
Asunto(s)
Infecciones por Klebsiella , Melatonina , Animales , Ratones , Tigeciclina/farmacología , Melatonina/farmacología , Melatonina/metabolismo , Minociclina/farmacología , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Farmacorresistencia Bacteriana/genética , Proteínas de Transporte de Membrana/genética , Antibacterianos/uso terapéutico , Adyuvantes Inmunológicos , Adyuvantes Farmacéuticos , Pruebas de Sensibilidad Microbiana , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismoRESUMEN
BACKGROUND: Avian pathogenic Escherichia coli (APEC) causes avian colibacillosis, which results in economic and welfare costs in the poultry industry worldwide. The pathogenesis of avian pathogenic E. coli strains is not well defined. Here, the function of an outer membrane protein encoded by the ireA gene of avian pathogenic E. coli strain DE205B was investigated. RESULTS: The ireA gene was distributed in 32.9 % (46/140) of tested E. coli strains, with high percentages in the phylogenetic ECOR groups B2 (58.8 %, 10/17) and D (55.9 %, 19/34). The gene expression level of ireA of APEC strain DE205B in high Fe M9 media was 1.8 times higher (P < 0.05) than that in low Fe M9 media. An ireA deletion mutant and complementary strain were constructed. Compared with the wild-type strain DE205B, the expression of most ferric uptake genes in the ireA deletion mutant were significantly upregulated (P < 0.05). The adhesion ability of the ireA deletion mutant to DF-1 cells was significantly decreased. The survival rate of ireA deletion mutant was reduced 21.17 % (P < 0.01), 25.42 (P < 0.05) and 70.0 % (P < 0.01) under alkali, high osmolarity, and low temperature (4 °C) conditions, respectively, compared with the wild-type strain. CONCLUSIONS: The results suggested that the protein encoded by the iron-regulated gene ireA has roles in adhesion and stress resistance in avian pathogenic E. coli.