Isoalantolactone restores the sensitivity of gram-negative Enterobacteriaceae carrying MCR-1 to carbapenems.

Polymyxin B has been re-applied to the clinic as the final choice for the treatment of multidrug-resistant gram-negative pathogenic infections, but the use of polymyxin B has been re-assessed because of the emergence and spread of the plasmid-mediated mcr-1 gene. The purpose of this study was to search for an MCR inhibitor synergistically acting with polymyxin to treat the infection caused by this pathogen. In this study, we used the broth microdilution checkerboard method to evaluate the synergistic effect of isoalantolactone (IAL) and polymyxin B on mcr-1-positive Enterobacteriaceae. Growth curve analysis, time-killing assays and a combined disc test were used to further verify the efficacy of the combined drug. Colonization of the thigh muscle in mice, survival experiments and lung tissue section observations was used to determine the effect of synergy in vivo after Klebsiella pneumoniae and Escherichia coli infection. We screened a natural compound, IAL, which can enhance the sensitivity of polymyxin B to mcr-1-positive Enterobacteriaceae. The results showed that the combined use of polymyxin B and IAL has a synergistic effect on mcr-1-positive Enterobacteriaceae, such as K pneumoniae and E coli, not only in vitro but also in vivo. Our results indicate that IAL is a natural compound with broad application prospects that can prolong the service life of polymyxin B and make outstanding contributions to the treatment of gram-negative Enterobacteriaceae infections resistant to polymyxin B.