Communications Biology
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2025
·Vol. 8
·期 1
·1-14
·
IF 5.1
Xu Tianqi,Fang Dan,Li Fulei,Wang Zhiqiang,Liu Yuan
Antimicrobial resistance poses a severe threat to human health, with colistin serving as a critical medication in clinical trials against multidrug-resistant Gram-negative bacteria. However, the efficacy of colistin is increasingly compromised due to the rise of MCR-positive bacteria worldwide. Here, we reveal a notable metabolic disparity between mcr -positive and -negative bacteria through transcriptome and metabolomics analysis. Specifically, pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, was significantly diminished in mcr -positive bacteria. Conversely, supplementing with PLP could reverse the metabolic profile of drug-resistant bacteria and effectively restore colistin’s bactericidal properties. Mechanistically, PLP was found to augment bacterial proton motive force by inhibiting the Kdp transport system, a bacterial K + transport ATPase, thereby facilitating the binding of the positively charged colistin to the negatively charged bacterial membrane components. Furthermore, PLP supplementation triggers ferroptosis-like death by accumulating ferrous ions and inducing lipid peroxidation. These two modes of action collectively resensitize mcr -harboring Gram-negative bacteria to colistin therapy. Altogether, our study provides a novel metabolic-driven antibiotic sensitization strategy to tackle antibiotic resistance and identifies a potentially safe antibiotic synergist.
研究领域:
微生物学
·
药理学
·
代谢组学
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DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Jinju Cai,Jingru Shi,Chen Chen,Mengping He,Zhiqiang Wang,Yuan Liu
The emergence and prevalence of mobile colistin resistance gene mcr have dramatically compromised the clinical efficacy of colistin, a cyclopeptide antibiotic considered to be the last option for treating different-to-treat infections. The combination strategy provides a productive and cost-effective strategy to expand the lifespan of existing antibiotics. Structural-activity relationship analysis of polymyxins indicates that the fatty acyl chain plays an indispensable role in their antibacterial activity. Herein, it is revealed that three saturated fatty acids (SFAs), especially sodium caprate (SC), substantially potentiate the antibacterial activity of colistin against mcr- positive bacteria. The combination of SFAs and colistin effectively inhibits biofilm formation and eliminates matured biofilms, and is capable of preventing the emergence and spread of mobile colistin resistance. Mechanistically, the addition of SFAs reduces lipopolysaccharide (LPS) modification by simultaneously promoting LPS biosynthesis and inhibiting the activity of MCR enzyme, enhance bacterial membrane damage, and impair the proton motive force-dependent efflux pump, thereby boosting the action of colistin. In three animal models of infection by mcr -positive pathogens, SC combined with colistin exhibit an excellent therapeutic effect. These findings indicate the therapeutic potential of SFAs as novel antibiotic adjuvants for the treatment of infections caused by multidrug-resistant bacteria in combination with colistin.
研究领域:
药理学
·
微生物学
·
传染病学
·
分子生物学
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DOI
PubMed
高影响因子
Research
·
2023
·
IF 11
Tianqi Xu,Dan Fang,Fulei Li,Zhiqiang Wang,Yuan Liu
The emergence of antibiotic tolerance, characterized by the prolonged survival of bacteria following antibiotic exposure, in natural bacterial populations, especially in pathogens carrying antibiotic resistance genes, has been an increasing threat to public health. However, the major causes contributing to the formation of antibiotic tolerance and underlying molecular mechanisms are yet poorly understood. Herein, we show that potassium sorbate (PS), a widely used food additive, triggers a high level of fluoroquinolone tolerance in bacteria carrying mobile colistin resistance gene mcr. Mechanistic studies demonstrate that PS treatment results in the accumulation of intracellular fumarate, which activates bacterial two-component system and decreases the expression level of outer membrane protein OmpF, thereby reducing the uptake of ciprofloxacin. In addition, the supplementation of PS inhibits aerobic respiration, reduces reactive oxygen species production and alleviates DNA damage caused by bactericidal antibiotics. Furthermore, we demonstrate that succinate, an intermediate product of the tricarboxylic acid cycle, overcomes PS-mediated ciprofloxacin tolerance. In multiple animal models, ciprofloxacin treatment displays failure outcomes in PS preadministrated animals, including comparable survival and bacterial loads with the vehicle group. Taken together, our works offer novel mechanistic insights into the development of antibiotic tolerance and uncover potential risks associated with PS use.
研究领域:
微生物学
·
药理学
·
公共卫生
·
分子生物学
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DOI
高影响因子
ACS Nano
·
2023
·
IF 17.1
Huimin Zhao,Lan-lan Zhong,Chuan Yang,Ning Tang,Yanwei He,Wan He,Zihan Zhao,Changbu Wu,Peiyan Yuan,Yi Yan Yang,Guo-bao Tian,Xin Ding
Colistin is the last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections that are untreatable by other clinically available antibiotics. However, the recently merged plasmid-borne gene mobilized colistin resistance (mcr) leads to modification of the colistin target (i.e., bacterial membrane), greatly compromising the therapy outcome of colistin. To address this unmet clinical need, a nanocomplex (CMS-pEt_20 NP) of anionic prodrug colistin methanesulfonate (CMS) and guanidinium-functionalized cationic polymer pEt_20 is developed through facile self-assembly for co-delivering an antibiotic and antimicrobial polymer with membrane affinity to reverse colistin resistance. The CMS-pEt_20 NP formation enables reversal of colistin resistance and complete killing of clinically isolated mcr-positive colistin-resistant bacteria including MDR E. coli and K. pneumoniae, while monotreatment of polymer or antibiotic at equivalent doses exhibits no antibacterial activity. Mechanistic studies reveal that the CMS-pEt_20 NP enhanced the affinity of delivered CMS to the modified membrane of colistin-resistant bacteria, reviving the membrane lytic property of colistin. The increased membrane permeability caused by colistin in turn promotes an influx of pEt_20 to generate intracellular ROS stress, resulting in elimination of colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis infection model demonstrates the excellent therapeutic efficacy of CMS-pEt_20 NP with 100% survival of the infected mouse. In addition, the nanocomplex is proven not toxic both in vitro and in vivo. Taken together, the self-assembled antibiotic–polymer nanocomplex with two complementary antibacterial mechanisms successfully reverses the colistin resistance phenotype in bacteria, and it can be a potential strategy to treat untreatable colistin-resistant MDR bacterial infections.
研究领域:
药学
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纳米技术
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微生物学
·
传染病学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）