AUTHOR=Cui Qi , Yu Han-Dong , Xu Qi-Jun , Liu Yue , Wang Yu-Ting , Li Peng-Hui , Kong Ling-Cong , Zhang Hai-Peng , Jiang Xiu-Yun , Giuliodori Anna Maria , Fabbretti Attilio , He Cheng-Guang , Ma Hong-Xia 

TITLE=Antibiotic synergist OM19r reverses aminoglycoside resistance in multidrug-resistant Escherichia coli

JOURNAL=Frontiers in Microbiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1144946

DOI=10.3389/fmicb.2023.1144946

ISSN=1664-302X

ABSTRACT=<sec><title>Introduction</title><p>The continued emergence and spread of multidrug-resistant (MDR) bacterial pathogens require a new strategy to improve the efficacy of existing antibiotics. Proline-rich antimicrobial peptides (PrAMPs) could also be used as antibacterial synergists due to their unique mechanism of action.</p></sec><sec><title>Methods</title><p>Utilizing a series of experiments on membrane permeability, <italic>In vitro</italic> protein synthesis, <italic>In vitro</italic> transcription and mRNA translation, to further elucidate the synergistic mechanism of OM19r combined with gentamicin.</p></sec><sec><title>Results</title><p>A proline-rich antimicrobial peptide OM19r was identified in this study and its efficacy against <italic>Escherichia coli</italic> B2 (<italic>E. coli</italic> B2) was evaluated on multiple aspects. OM19r increased antibacterial activity of gentamicin against multidrug-resistance <italic>E. coli</italic> B2 by 64 folds, when used in combination with aminoglycoside antibiotics. Mechanistically, OM19r induced change of inner membrane permeability and inhibited translational elongation of protein synthesis by entering to <italic>E. coli</italic> B2 via intimal transporter SbmA. OM19r also facilitated the accumulation of intracellular reactive oxygen species (ROS). In animal models, OM19r significantly improved the efficacy of gentamicin against <italic>E. coli</italic> B2.</p></sec><sec><title>Discussion</title><p>Our study reveals that OM19r combined with GEN had a strong synergistic inhibitory effect against multi-drug resistant <italic>E. coli</italic> B2. OM19r and GEN inhibited translation elongation and initiation, respectively, and ultimately affected the normal protein synthesis of bacteria. These findings provide a potential therapeutic option against multidrug-resistant <italic>E. coli</italic>.</p></sec>