Novel nitroxoline derivative combating resistant bacterial infections through outer membrane disruption and competitive NDM-1 inhibition

New Delhi metallo- -lactamase-1 (NDM-1) has rapidly disseminated worldwide, leading to multidrug resistance and worse clinical prognosis. Designing and developing effective NDM-1 inhibitors is a critical and urgent challenge. In this study, we constructed a library of long-lasting nitroxoline deriva...

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Published in:Emerging microbes & infections 2024-12, Vol.13 (1), p.2294854
Main Authors: He, Peng, Huang, Sijing, Wang, Rui, Yang, Yunkai, Yang, Shangye, Wang, Yue, Qi, Mengya, Li, Jiyang, Liu, Xiaofen, Zhang, Xuyao, Feng, Meiqing
Format: Article
Language:English
Subjects:
Animals
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
antibiotic resistance
ASN-1733
Bacteria
Bacterial Infections
beta-Lactamases - metabolism
Drug Resistance and Novel Antimicrobial Agents
inhibitor
Meropenem - pharmacology
Mice
Microbial Sensitivity Tests
NDM-1
Nitroquinolines - pharmacology
Nitroxoline
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Summary:New Delhi metallo- -lactamase-1 (NDM-1) has rapidly disseminated worldwide, leading to multidrug resistance and worse clinical prognosis. Designing and developing effective NDM-1 inhibitors is a critical and urgent challenge. In this study, we constructed a library of long-lasting nitroxoline derivatives and identified ASN-1733 as a promising dual-functional antibiotic. ASN-1733 can effectively compete for Ca on the bacterial surface, causing the detachment of lipopolysaccharides (LPS), thereby compromising the outer membrane integrity and permeability and exhibiting broad-spectrum bactericidal activity. Moreover, ASN-1733 demonstrated wider therapeutic applications than nitroxoline in mouse sepsis, thigh and mild abdominal infections. Furthermore, ASN-1733 can effectively inhibit the hydrolytic capability of NDM-1 and exhibits synergistic killing effects in combination with meropenem against NDM-1 positive bacteria. Mechanistic studies using enzymatic experiments and computer simulations revealed that ASN-1733 can bind to key residues on Loop10 of NDM-1, hindering substrate entry into the enzyme's active site and achieving potent inhibitory activity (K = 0.22 µM), even in the presence of excessive Zn . These findings elucidate the antibacterial mechanism of nitroxoline and its derivatives, expand their potential application in the field of antibacterial agents and provide new insights into the development of novel NDM-1 inhibitors.
ISSN:2222-1751
2222-1751
DOI:10.1080/22221751.2023.2294854