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大自然的秘密武器:BPD-9以革命性的功效治疗结核病
2024-10-4 20:11
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大自然的秘密武器:BPD-9以革命性的功效治疗结核病

诸平

Natural-Drug-Plant-Medicine-Art-Concept.jpg

Fig. 1 Researchers have developed a new semi-synthetic compound, derived from the natural compound sanguinarine, showing potent activity against Mycobacterium tuberculosis, including drug-resistant strains. This breakthrough could lead to effective new treatments for tuberculosis, a major bacterial disease worldwide. Credit: SciTechDaily.com

Secondary-Tuberculosis-Infection-Anatomy-Image.jpg

Fig. 2 Tuberculosis (TB) is a highly infectious disease caused by the bacterium Mycobacterium tuberculosis. It primarily affects the lungs but can also impact other parts of the body. Characterized by symptoms such as persistent cough, fever, and weight loss, TB is spread through the air when infected individuals cough or sneeze.

Mycobacterium-Tuberculosis-Bacteria-Green.jpg

Fig. 3 Scanning electron micrograph of Mycobacterium tuberculosis bacteria, which cause TB. Credit: NIAID

据美国微生物学会American Society for Microbiology2024103日提供的消息,大自然的秘密武器:BPD-9以革命性的功效治疗结核病Nature’s Secret Weapon: BPD-9 Takes on Tuberculosis With Revolutionary Efficacy)。

一种名为BPD-9的新化合物已被证明可以有效地靶向耐药结核病(target drug-resistant tuberculosis),这种化合物是从天然抗菌药物血根碱(sanguinarine)中提取的。

导致结核病(tuberculosis简称TB)的结核分枝杆菌(Mycobacterium tuberculosis)是对公共卫生的重大威胁。一项新的研究发现,一种半合成化合物可以从天然化合物中提取,并显示出对结核分枝杆菌(M. tuberculosis,包括多重耐药菌株)的有效活性。这是朝着有效治疗结核病(TB)的新方法迈出的有希望的一步。

新型抗结核病化合物(Novel Anti-TB Compound

2024103日发表在美国微生物学会期刊《微生物学光谱》(Microbiology Spectrum)杂志网站上的一项新研究表明,一种新的半合成化合物可以从天然化合物中提取出来,对包括多重耐药菌株在内的结核分枝杆菌(Mycobacterium tuberculosis)产生有效的活性。该化合物为开发新型强效抗结核药物提供了一个很有前景的化学支架。原文详见:Yi Chu Liang, Zhiqi Sun, Chen Lu, Andréanne Lupien, Zhongliang Xu, Stefania Berton, Peng Xu, Marcel A. Behr, Weibo Yang, Jim Sun. Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant Mycobacterium tuberculosis. Microbiology Spectrum, 2024 Oct 3: e0124624. DOI: 10.1128/spectrum.01246-24

参与此项研究的有来自加拿大温哥华英属哥伦比亚大学(University of British Columbia, Vancouver, Canada)、加拿大渥太华大学(University of Ottawa, Ottawa, Canada)、中国科学院上海药物研究所(Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China)、中国科学院大学(University of Chinese Academy of Sciences, Beijing, China)、加拿大麦吉尔大学保健中心研究所(Research Institute of the McGill University Health Centre, Montréal, Canada)、加拿大麦吉尔国际结核病中心(McGill International TB Centre, Montréal, Canada)、加拿大麦吉尔大学(McGill University, Montréal, Canada)、加拿大麦吉尔大学保健中心(McGill University Health Centre, Montréal, Canada)、中国科学院大学杭州高等研究院(Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China)的研究人员。.

结核分枝杆菌(M. tuberculosis)是导致结核病(TB)的病原体,是全球细菌性疾病相关死亡的主要原因。目前用于治疗结核病的抗生素方案已经过时,需要较长的疗程,并且有产生耐药性的风险。

创新抗生素的发现(Innovative Antibiotic Discovery

在这项新研究中,研究人员寻找了一种针对结核分枝杆菌的新型抗生素,这种抗生素也可能对耐药菌株有效。在药物发现方面,寻找新抗生素的一个有价值的起点是在植物、真菌和细菌等生物产生的天然化合物的世界里。

血根碱(Sanguinarine)是一种已知具有抗菌特性的天然化合物,是从一种原产于北美的草本开花植物中提取出来的。血根碱已被用于动物的传统和替代药物,但其毒性使其不适合作为药物用于人类。

这组研究人员利用药物化学原理重新设计了血根碱,以生产一种毒性更低、更有效的抗菌化合物。在试管和小鼠的研究中,被称为BPD-9的改进版血根碱能够杀死对临床用于治疗结核病的所有一线抗生素都具有耐药性的结核分枝杆菌菌株。

此外BPD-9对非复制(休眠)和细胞内结核分枝杆菌有效,这是限制当前抗结核药物有效性的两个关键方面。研究人员还发现,BPD-9只对与结核分枝杆菌属相同的致病菌有效,这可能会避免大多数抗生素伤害的微生物群和其他有益细菌。

对未来结核病治疗的启示(Implications for Future TB Treatments

 “我们的研究结果表明,一种新的化学实体在对抗结核分枝杆菌方面具有独特的特性,可能会进一步用于临床转化,”相应研究的作者、英属哥伦比亚大学微生物学和免疫学系(Department of Microbiology and Immunology at The University of British Columbia)助理教授Jim Sun博士说。

“我们发现这种新化合物对分枝杆菌属的其他成员有效,这可能也证明在对抗由非结核分枝杆菌引起的致命肺部感染方面是有价值的。众所周知,非结核分枝杆菌对大多数抗生素都具有耐药性。人们还可以推测,BPD-9可能以一种不同于现有抗结核药物的方式杀死结核分枝杆菌。”

该研究是与中国科学院上海药物研究所杨伟波Weibo Yang)博士的药物化学团队以及加拿大麦吉尔大学马塞尔·贝尔(Marcel Behr)医学博士和Andréanne Lupien博士的细菌遗传学团队合作进行的。这项研究得到了加拿大卫生研究院(Canadian Institutes of Health Research - CIHR和加拿大国家疗养院协会National Sanitarium Association的资助。

上述介绍,仅供参考。欲了解更多信息,敬请注意浏览原文或者相关报道

Abstract

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 ~2 to 10 µM) against multiple Mycobacterium strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of Mycobacterium bovis BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to Mycobacterium spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.IMPORTANCEThe emergence of drug-resistant tuberculosis (TB) is a serious global health threat. There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug-resistant Mycobacterium tuberculosis (Mtb). This study shows that novel semi-synthetic compounds can be derived from natural compounds to produce potent activity against Mtb. Importantly, the identified compounds have narrow spectrum activity against Mycobacterium species, including clinical multidrug-resistant (MDR) strains, are effective in infected macrophages and against non-replicating Mtb (NR-Mtb), and show anti-mycobacterial activity in mice. These new compounds provide promising chemical scaffolds to develop potent anti-Mtb drugs of the future.

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