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Cell:细菌耐药性研究产生重大进展

2018-01-11  来源:艾兰博曼医学网    编辑:陌莉花开
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丹麦技术大学诺和诺德基金会生物可持续性研究中心的研究人员报告称,对假单胞菌的产生耐药性的囊性纤维化(CF)患者对其他类型的抗生素产生可预测的敏感性。科学家相信,这一发现可能


丹麦技术大学诺和诺德基金会生物可持续性研究中心的研究人员报告称,对假单胞菌的产生耐药性的囊性纤维化(CF)患者对其他类型的抗生素产生可预测的敏感性。科学家相信,这一发现可能会产生优化慢性感染的新疗法。

诺和诺德基金会生物可持续研究中心教授及科学主任Morten Sommer博士表示,通过研究他们发现在多重耐药性的铜绿假单胞菌感染中存在广泛的抗生素敏感性,这为受限抗生素的治疗大大提高了可能性,甚至可能发生逆转,这对于治疗一些慢性感染包括囊性纤维化患者的终生肺部感染等非常有帮助。

研究人员发现,在哥本哈根Rigshospitalet的囊性纤维化诊所里,几十年临床分离的多重耐药的病原体菌株均保留了对许多抗生素敏感的特性。相关研究结果发表在《Cell》上,接下来的工作可能为确定那些引起药物敏感性的潜在突变。

慢性铜绿假单胞菌感染可以规避抗生素的治疗,并导致囊性纤维化患者死亡率的增加。在这项新的研究中,研究人员发现体外铜绿假单胞菌对临床相关抗生素耐药性的演变导致了不同程度的表型收敛。这些状态与对这几种抗生素的并生性敏感性相关,并且由抗生素的抗性基因(包括转录调节因子nfxB)的突变编码。囊性纤维化患者分离株的纵向分析揭示了类似个确定性的表型状态,这与患者特定亚型的消失有关。

在抗生素治疗过程中对囊性纤维化患者慢性铜绿假单胞菌感染进行深入研发现显著的基因型和表现型趋同性。而且,nfxB突变的氟喹诺酮抗性亚群通过抗生素治疗治疗可被根除。这项研究也支持了原来的数据假设,慢性感染的抗生素治疗可以通过通过靶向特定突变相关的表型状态来优化,以改善慢性感染的治疗功能。

诺和诺德基金会中心的高级研究员Lejla Imamovic博士表示,针对与特定突变相关的表型状态可能会对抗生素的敏感性产生重大影响,据此可以为每个患者制定个性化的诊疗策略。研究结果表明,对于一些抗生素,暴露和随后的抗性进化导致取向特定的表型状态。因此,并生敏感性可能对量身定做并优化慢性感染特别有用。

目前,引起慢性感染的病原体对抗生素治疗的耐药性日益增强。然而,临床应用药物间产生的并生敏感性揭示,慢性细菌感染所产生的耐药性会随着时间的推移而发生改变,以适应不同的药物治疗。依据这一点,设定与特定药物并生敏感性的诊断标志物,可以显著改善慢性感染患者的治疗。

这些研究结果的发现与已经在临床上使用的药物相关,仅仅对医生现在的治疗经验稍作改变,便可获得治疗益处。为了在临床上充分利用这项研究结果,更大规模的对照临床试验也是非常重要的。

英文原文:

Significant Advance Reported in the Battle against Multidrug-Resistant Bacteria


Researchers from the Novo Nordisk Foundation Center for Biosustainability at the Technical University of Denmark report that antibiotic-resistant Pseudomonas infections in cystic fibrosis (CF) patients show predictable sensitivities to other classes of antibiotics. The scientists believe that this finding could lead to new ways of optimizing treatments for chronic infections.

"Our discovery of widespread antibiotic sensitivities in the multidrug-resistant pathogen Pseudomonas aeruginosa opens up the opportunity to limit the development of antibiotic resistance and perhaps even revert it. This could be important for the treatment of several chronic infections, including the life-long lung infections of patients with cystic fibrosis," says Morten Sommer, Ph.D., professor and scientific director at the Novo Nordisk Foundation Center for Biosustainability,

The researchers found a number of antibiotic vulnerabilities of multidrug-resistant pathogens were preserved across clinical isolates isolated over decades at the CF clinic at Rigshospitalet in Copenhagen. In a study (“Drug-Driven Phenotypic Convergence Supports Rational Treatment Strategies of Chronic Infections”) published in Cell, the team noted that it then became possible to identify the underlying mutations that caused the sensitivity.

“Chronic Pseudomonas aeruginosa infections evade antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P. aeruginosa toward clinically relevant antibiotics leads to phenotypic convergence toward distinct states. These states are associated with collateral sensitivity toward several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients,” write the investigators.

“In-depth investigation of chronic P. aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.”

"Targeting vulnerabilities of phenotypic states related to specific mutations could potentially have a huge impact because it makes it possible to make a more personalized treatment strategy for each patient," says Lejla Imamovic, Ph.D., senior researcher at the Novo Nordisk Foundation Center for Biosustainability. "Results indicate that for some antibiotics, exposure and subsequent resistance evolution leads to convergence toward specific phenotypes states. Thus, collateral sensitivity may be particularly useful for optimizing treatments of chronic infections since their nature and severity warrants and requires tailored treatment strategies."

The current thinking on resistance evolution suggests that pathogens causing chronic infections become increasingly resistant in response to antibiotic treatment, according to Dr. Imamovic. Yet, the findings of widespread collateral sensitivity interactions among clinically applied drugs anticipate that the resistance profiles of chronic infecting bacteria would fluctuate over time in response to different drug exposures, explains Dr. Sommer.

"Our research supports the notion that treatment of chronically infected patients could be significantly improved based on specific diagnostic markers that are associated with a collateral sensitivity to specific drugs," he says.

Some of the team’s findings relate to drugs that are already used clinically and it is possible that benefits can be gained simply by making slight changes to the empirical treatment prescribed by physicians now, adds Dr. Sommer.

But he emphasizes that "larger controlled clinical trials will also be important in order to fully exploit these findings in the clinic."



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