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

Abstract

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.

Back to the Roots—An Overview of the Chemical Composition and Bioactivity of Selected Root-Essential Oils

“…Furthermore, it could be shown that low micromolecular concentrations (1–20 µM) of ALT intensified the uptake of S. aureus and thus stimulated immune functions of macrophages [ 185 ]. However, IAL has also recently been found to exert strong synergistic effects with carbapenems (polymyxin B or colistin) in the treatment of mcr-1-positive Enterobacteriaceae such as K. pneumoniae and E. coli in vivo and in vitro [ 186 ].…”

Global Epidemiology and Genetic Environment of mcr genes: A One Health Systematic Review of Current and Emerging Trends

“…Natural/organic compounds identified with a synergistic effect on colistin include Honokiol 186 , Isoalantolactone (IAL) 187 , Calycosin 188 and Eugenol 189 . Honokiol was derived from the dry skin and bark of Magnolia officinalis 186 , IAL is the main sesquiterpene lactone from Radix inulae and other plants 187 , Calycosin is a flavonoid from a direct root extract of the traditional Chinese medicinal herb, Radix astragali.…”

“…Other novel compounds that have been reported to restore susceptibility of polymyxins in mcr-1 producing isolates includes the novel MCR-1 inhibitor, Osthole Natural/organic compounds identified with a synergistic effect on colistin include Honokiol 186 , Isoalantolactone (IAL) 187 , Calycosin 188 and Eugenol 189 . Honokiol was derived from the dry skin and bark of Magnolia officinalis 186 , IAL is the main sesquiterpene lactone from Radix inulae and other plants 187 , Calycosin is a flavonoid from a direct root extract of the traditional Chinese medicinal herb, Radix astragali. 188 Lastly, Eugenol is a phenylpropanoid, an essential oil isolated from plants 190 .…”

A novel bactericidal small molecule, STK-35, and its derivative, STK-66, as antibacterial agents against Gram-negative pathogenic bacteria in vitro and in vivo

“…2020) (Lu et al . 2020). As for toxicity determination in vivo , the mice ( n = 9) were intraperitoneally injected with 30 mg kg −1 of polymyxin B or STK‐35/66 and observed for consecutive 7 days.…”

“…and 10 mg kg −1 polymyxin B (subcutaneously, s.c.) were administered as the vehicle and positive groups, respectively. The survival of infected mice was monitored twice a day for seven consecutive days (She et al 2020) (Lu et al 2020). As for toxicity determination in vivo, the mice (n = 9) were intraperitoneally injected with 30 mg kg −1 of polymyxin B or STK-35/66 and observed for consecutive 7 days.…”