AUTHOR=Yu Fan , Han Xiao-Le , Zhu Jiahua , Dai Le , Liu Shuzhi , Liu Qing-Pei , Yang Jian , Sun Yue , Guo Lan-Ping , Yang Xiao-Long 

TITLE=A natural product noraucupatin against multidrug-resistant Enterococcus faecium: an inhibition mechanism study

JOURNAL=Frontiers in Chemical Biology

VOLUME=2

YEAR=2023

URL=https://www.frontiersin.org/journals/chemical-biology/articles/10.3389/fchbi.2023.1181137

DOI=10.3389/fchbi.2023.1181137

ISSN=2813-530X

ABSTRACT=<p><bold>Background:</bold> This work elucidates the antimicrobial activity and mechanism of action of the natural product noraucupatin against MDR <italic>Enterococcus faecium</italic>. <italic>E. faecium</italic> has become a major opportunistic pathogen with the worldwide spread of multidrug-resistant (MDR) isolates, especially vancomycin-resistant <italic>enterococci</italic> (VRE), belongs to “ESKAPE” organisms causing significant problems widely. Hence, there is a pressing need to discover new promising drugs or alternative therapies. Fortunately, we found a natural product noraucupatin (C<sub>13</sub>H<sub>12</sub>O<sub>3</sub>, a biphenyl compound) with “extremely encouraging” anti-clinical drug-resistant bacterial activity isolated from <italic>yeast</italic>-induced <italic>Rowan</italic> suspension cells. A comprehensive and in-depth exploration of antimicrobial mechanisms will bring fresh insights for researchers to develop novel antimicrobial strategies against MDR bacteria.</p><p><bold>Methods:</bold> The antibacterial effect of noraucupatin against MDR <italic>E. faecium</italic> is investigated from a microbial metabolism perspective using microcalorimetry. The antibacterial effect is determined based on the thermodynamic parameters. Based on spectroscopic techniques, microscopy techniques and confocal scanning laser microscopy with membrane probes, the antibacterial mechanism is elucidated definitely.</p><p><bold>Results:</bold> Comparing with the <italic>IC</italic><sub>50</sub> of noraucupatin against MDR <italic>Enterococcus faecalis</italic>, MRSA, CRPA, the <italic>IC</italic><sub>50</sub> of noraucupatin against MDR <italic>E. faecium</italic> was just 67.54 μM. The growth rate of MDR <italic>E. faecium</italic> decreases with the increase of concentration of noraucupatin. The bacterial intracellular structure entirely collapses and the slurries flow out under the influence of high levels of noraucupatin by TEM. The changes of membrane potential, permeability and evidences of nucleic acid leakage was obtained by CSLM and UV, the mechanism of noraucupatin against MDR <italic>E. faecium</italic> we explored.</p><p><bold>Conclusion:</bold> The present study highlights the excellent antibacterial activity of noraucupatin against MDR <italic>E. faecium</italic> by altering the permeability of the membrane and disrupting the membrane potential leading to electrolyte permeation. In addition, noraucupatin has excellent biocompatibility through its haemolytic activity in rabbit erythrocyte. These findings suggest that noraucupatin could be used in infectious diseases caused by MDR <italic>E. faecium.</italic></p>