Identification of a Novel ArnT Inhibitor That Restores Polymyxin B Susceptibility in <i>Klebsiella pneumoniae</i> by Blocking Lipid A Modification

<p dir="ltr"><a href="" target="_blank">Polymyxin B is the last resort against the worsening antimicrobial resistance of bacterial, but its clinical application is threatened by drug resistance, particularly in <i>Klebsiella pneumoniae</i>. </a><a href="" target="_blank">Therefore, </a>developing adjuvants that can restore polymyxin B sensitivity is urgently needed. ArnT is a critical lipid A modifying enzyme that alters the surface properties of LPS, thereby inducing resistance to polymyxin B and assisting bacteria in evading attacks from the human immune system.

This study used AlphaFold2 to predict the structure of ArnT in <i>K. pneumoniae</i> and the virtual screening from a million-compound library to discovered that nonyl β-D-glucopyranoside (NG) is an effective inhibitor of ArnT. The strong affinity of NG for the ArnT active site, composed of residues I138, L182, E241, R245, and Y316, was verified <i>in vitro</i> and <i>in vivo</i>. It represents the primary mechanism by which NG restores polymyxin B susceptibility in <i>K. pneumoniae</i>.