AUTHOR=Zhou Yonglin , Wang Tingting , Guo Yan , Liu Shui , Wang Jianfeng , Shen Yingbo , Tang Shusheng , Wang Yang , Deng Xuming 

TITLE=In Vitro/Vivo Activity of Potential MCR-1 Inhibitor in Combination With Colistin Againsts mcr-1-Positive Klebsiella pneumonia

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.01615

DOI=10.3389/fmicb.2018.01615

ISSN=1664-302X

ABSTRACT=<p>Carbapenem resistance among strains of the nosocomial pathogen <italic>Klebsiella pneumoniae</italic> is increasing worldwide, causing serious clinical infections and higher mortality rates. Polymyxins are some of the few “last resort” options for treatment of carbapenem-resistant <italic>Enterobacteriaceae</italic>, including <italic>K. pneumoniae</italic>, however, the emergence of plasmid-mediated colistin resistance gene <italic>mcr-1</italic> has largely rendered polymyxin-class antibiotics ineffective in a clinical setting. We previously identified a natural compound, pterostilbene, which has a synergistic effect in combination with polymyxins. Here, we aimed to determine whether pterostilbene application can restore the bactericidal activity of polymyxins against <italic>mcr-1-</italic>positive <italic>K. pneumoniae</italic>. Checkerboard MIC studies confirmed that pterostilbene reduces the MIC of colistin against <italic>mcr-1-</italic>positive clinical <italic>K. pneumoniae</italic> isolates, with the bacteria going from resistant to sensitive, and also demonstrated a synergistic effect with colistin (FIC index = 0.11 ± 0.04 or 0.28 ± 0.00). Time-killing assays showed that individually, both pterostilbene and colistin failed to eradicate <italic>K. pneumoniae</italic> strains, while in combination, the two drugs effectively eliminated <italic>K. pneumoniae</italic> ZJ02 and <italic>K. pneumoniae</italic> ZJ05 by 1–3 h post-inoculation. The combined disk test also showed increases in the zones of inhibition only for <italic>mcr-1-</italic>positive <italic>Escherichia coli</italic> and <italic>K. pneumoniae</italic> isolates. A mouse infection model demonstrated that the survival rate of mice at 7 days post-intraperitoneal injection with a lethal dose of <italic>K. pneumoniae</italic> ZJ05 was significantly promoted from 0 to 67% following combination therapy. This is the first time a MCR-1 inhibitor has successfully been used in combination with colistin against human clinical MCR-1 producing <italic>K. pneumoniae</italic> ZJ05 isolate.</p>