ORIGINAL RESEARCH article
Front. Cell. Infect. Microbiol.
Sec. Antibiotic Resistance and New Antimicrobial drugs
Volume 15 - 2025 | doi: 10.3389/fcimb.2025.1658194
Nicorandil Reduces the Antimicrobial Effectiveness of Polymyxin E against Klebsiella pneumoniae by Decreasing Reactive Oxygen Species Accumulation
Provisionally accepted
Rongqing ZhuFangxin LuoChenxi YuanZiqian FangYaqin Guo
Meng BaoDongmei ZhaoYanyan Liu
Yi YangYasheng Li
Jiabin Li*Liang Yu*- Department of Infectious Diseases, First Affiliated Hospital, Anhui Medical University, Hefei, China
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Nitric oxide (NO) plays a crucial role in bacterial physiology and survival, particularly in relation to antibiotic resistance. The protective role of NO against antibiotics is intricate, and the potential antagonistic interactions between NO donors and polymyxin E remain largely unexplored. This study aimed to evaluate the antagonistic effects of nicorandil, a NO donor, on the bactericidal activity of polymyxin E against Klebsiella pneumoniae. Methods: Thirty clinical strains were identified as multidrug-resistant K. pneumoniae using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The antimicrobial efficacy of polymyxin E combined with nicorandil against K. pneumoniae was evaluated through in vitro rapid killing assays and growth curve analyses, and in vivo using a murine pulmonary infection model and a Galleria mellonella larvae infection model. The release of NO by nicorandil was confirmed via reactive nitrogen species (RNS) assays. The impact of NO on oxidative stress responses induced by polymyxin E was evaluated using reactive oxygen species (ROS) assays and RT-qPCR. Results: Nicorandil counteracted the bactericidal effects of polymyxin E in 16 out of 30 clinical isolates of K. pneumoniae. Notably, the most pronounced effects were observed in the K. pneumoniae strain GN 191035. In this context, the release of NO from nicorandil conferred protection to the bacteria against oxidative stress by reducing ROS, as demonstrated by a murine model of pulmonary infection and a Galleria mellonella larvae infection model. Conclusions: Our study further elucidated that nicorandil treatment mitigates the bactericidal efficacy of polymyxin E against K. pneumoniae. These findings highlight the significant risk of increased bacterial infections associated with the concurrent administration of nicorandil and polymyxin E.
Keywords: Nicorandil, Polymyxin E, Klebsiella pneumoniae, Reactive Oxygen Species, Nitric Oxide
Received: 02 Jul 2025; Accepted: 01 Sep 2025.
Copyright: © 2025 Zhu, Luo, Yuan, Fang, Guo, Bao, Zhao, Liu, Yang, Li, Li and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jiabin Li, Department of Infectious Diseases, First Affiliated Hospital, Anhui Medical University, Hefei, China
Liang Yu, Department of Infectious Diseases, First Affiliated Hospital, Anhui Medical University, Hefei, China
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