Mechanism of Action of Isopropoxy Benzene Guanidine against Multidrug-Resistant Pathogens

Li, Jie; Zhang, Xiufeng; Han, Ning; Wan, Peng; Zhao, Fei; Xu, Tiantian; Peng, Xianfeng; Xiong, Wenguang; Zeng, Zhenling

doi:10.1128/spectrum.03469-22

Cited by 10 publications

(12 citation statements)

References 52 publications

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“…Currently, a variety of colistin adjuvants have been discovered, including plant-derived ( Wang et al, 2018 ; Song et al, 2021 ), chemically synthesized ( Kathayat et al, 2020 ; Li et al, 2023 ), and FDA-approved ( Stokes et al, 2017 ; Torres et al, 2018 ). Among these, the discovery of new uses for FDA approved old drugs is cheaper and faster than the discovery of new drugs from scratch ( Boucher et al, 2013 ; Farha and Brown, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

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The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens

Li,

Han,

et al. 2024

Front. Pharmacol.

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Background:The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue.Methods:Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models.Results:In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive and -negative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models.Conclusion:These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.

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Section: Discussionmentioning

confidence: 99%

“…The standard strains for this study were purchased from the China General Microbiological Culture Collection Center (CGMCC), Escherichia coli SHP45 and other clinical strains were isolated and preserved by our laboratory. MG1655-Δ waaC was previously constructed in our laboratory ( Li et al, 2023 ).…”

Section: Methodsmentioning

confidence: 99%

The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens

Li,

Han,

et al. 2024

Front. Pharmacol.

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“…Thus, guanidine has been developed as the dominant structural motif in the design of novel drugs for the treatment of various infectious diseases [ 30 , 31 ]. IBG is a substituted benzoguanidine derivative with good antibacterial activity against Gram-positive and Gram-negative bacteria [ 13 , 14 , 15 ]. The purpose of this work was to study the metabolism of IBG for the first time by using in vitro methods and analytical tools.…”

Section: Discussionmentioning

confidence: 99%

“…Guanidine-containing compounds also have good antibacterial activity against drug-resistant bacteria [ 10 , 11 ]. Isopropoxy benzene guanidine (IBG) is a novel guanidine compound that not only exhibits effective antibacterial activity against Gram-positive bacteria but also restores the sensitivity of Gram-negative bacteria to colistin as an antibiotic adjuvant [ 12 , 13 , 14 , 15 ]. IBG is expected to be a new antibacterial drug for bacterial infections.…”

Section: Introductionmentioning

confidence: 99%

Metabolite Identification of Isopropoxy Benzene Guanidine in Rat Liver Microsomes by Using UHPLC-Q-TOF-MS/MS

Zhang

et al. 2023

IJMS

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Isopropoxy benzene guanidine (IBG) is a guanidine derivative with antibacterial activity against multidrug-resistant bacteria. A few studies have revealed the metabolism of IBG in animals. The aim of the current study was to identify potential metabolic pathways and metabolites of IBG. The detection and characterization of metabolites were performed with high-performance liquid chromatography tandem mass spectrometry (UHPLC-Q-TOF-MS/MS). Seven metabolites were identified from the microsomal incubated samples by using the UHPLC-Q-TOF-MS/MS system. The metabolic pathways of IBG in the rat liver microsomes involved O-dealkylation, oxygenation, cyclization, and hydrolysis. Hydroxylation was the main metabolic pathway of IBG in the liver microsomes. This research investigated the in vitro metabolism of IBG to provide a basis for the further pharmacology and toxicology of this compound.

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“…Many antimicrobial agents, including the cholic acid derivatives, contain a guanidine functional group. − Guanidines can be protonated and positively charged at physiological pH in a similar way to the antibacterial quaternary ammonium compounds (QAC). , Thus, a positively charged guanidine compound can facilitate the disruption of bacterial cell membranes through electrostatic interactions with the membrane anionic lipids . Since mammalian cells possess mainly neutral and uncharged lipids, guanidine compounds can selectively disrupt bacteria over mammalian cell membranes.…”

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confidence: 99%

Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics

Kim,

Hind,

Fernandes

et al. 2024

ACS Med. Chem. Lett.

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A new class of amphiphilic molecules, the lipoguanidines, designed as hybrids of guanidine and fatty acid compounds, has been synthesized and developed. The new molecules present both a guanidine polar head and a lipophilic tail that allow them to disrupt bacterial membranes and to sensitize Gram-negative bacteria to the action of the narrow-spectrum antibiotics rifampicin and novobiocin. The lipoguanidine 5g sensitizes Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to rifampicin, thereby reducing the antibiotic minimum inhibitory concentrations (MIC) up to 256-fold. Similarly, 5g is able to potentiate novobiocin up to 64-fold, thereby showing a broad spectrum of antibiotic potentiating activity. Toxicity and mechanism studies revealed the potential of 5g to work synergistically with rifampicin through the disruption of bacterial membranes without affecting eukaryotic cells.

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Mechanism of Action of Isopropoxy Benzene Guanidine against Multidrug-Resistant Pathogens

Abstract: As antibiotic discovery stagnates, the world is facing a growing menace from the emergence of bacteria that are resistant to almost all available antibiotics. The key to winning this race is to explore distinctive mechanisms of antibiotics.

Cited by 10 publications

References 52 publications

The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens

The synergistic antibacterial activity and mechanism of colistin-oxethazaine combination against gram-negative pathogens

Metabolite Identification of Isopropoxy Benzene Guanidine in Rat Liver Microsomes by Using UHPLC-Q-TOF-MS/MS

Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics

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