Discovery of a novel natural product inhibitor of Clostridioides difficile with potent activity in vitro and in vivo.
Discovery of a novel natural product inhibitor of Clostridioides difficile with potent activity in vitro and in vivo.
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DOI：
10.1371/journal.pone.0267859
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
艰难梭状芽胞杆菌感染是一个全球性的健康威胁，并且仍然是全世界医院获得性感染的主要原因。迅速增长的感染发病率和严重性，加上高复发率，产生了对新疗法的迫切需求。在这里，我们报道了一种新型的天然产物支架，作为一种潜在的抗菌药物，在体外和体内都具有抗毒力和强大的活性。对1,000个纯化天然产物进行全细胞表型筛选，鉴定出6个化合物对艰难梭菌有较强的抑制活性(最低抑菌浓度为0.03~2μg/ml)。这6个化合物对人结直肠癌细胞均无毒性。天然产物化合物还抑制关键毒素TcdA和TcdB的产生，TcdA和TcdB是艰难梭菌感染病理的关键毒力决定因素。此外，这些化合物具有快速杀菌活性，在减少艰难梭菌体外高接种量方面优于标准护理抗生素万古霉素。此外，艰难梭菌感染的小鼠模型显示，化合物NP-003875对感染的小鼠具有100%的保护作用，使其免受疾病的临床表现。总而言之，本研究为进一步研究天然产物NP-003875作为艰难梭菌感染的潜在治疗选择奠定了基础。
Clostridioides difficile infection is a global health threat and remains the primary cause of hospital-acquired infections worldwide. The burgeoning incidence and severity of infections coupled with high rates of recurrence have created an urgent need for novel therapeutics. Here, we report a novel natural product scaffold as a potential anticlostridial lead with antivirulence properties and potent activity both in vitro and in vivo. A whole cell phenotypic screening of 1,000 purified natural products identified 6 compounds with potent activity against C. difficile (minimum inhibitory concentration (MIC) range from 0.03 to 2 μg/ml). All these 6 compounds were non-toxic to human colorectal cells. The natural product compounds also inhibited the production of key toxins, TcdA and TcdB, the key virulence determinants of C. difficile infection pathology. Additionally, the compounds exhibited rapid bactericidal activity and were superior to the standard-of-care antibiotic vancomycin, in reducing a high inoculum of C. difficile in vitro. Furthermore, a murine model of C. difficile infection revealed that compound NP-003875 conferred 100% protection to the infected mice from clinical manifestations of the disease. Collectively, the current study lays the foundation for further investigation of the natural product NP-003875 as a potential therapeutic choice for C. difficile infection.
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影响因子：
17.1
作者：
Kirk JA;Gebhart D;Buckley AM;Lok S;Scholl D;Douce GR;Govoni GR;Fagan RP
通讯作者：
Fagan RP
影响因子：
7.3
作者：
Naclerio, George A.;Abutaleb, Nader S.;Li, Daoyi;Seleem, Mohamed N.;Sintim, Herman O.
通讯作者：
Sintim, Herman O.
影响因子：
11.8
作者：
El Feghaly, Rana E.;Stauber, Jennifer L.;Haslam, David B.
通讯作者：
Haslam, David B.
DOI：
10.1093/jac/dkv006
发表时间：
2015
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Corbett D;Wise A;Birchall S;Warn P;Baines SD;Crowther G;Freeman J;Chilton CH;Vernon J;Wilcox MH;Vickers RJ
通讯作者：
Vickers RJ
影响因子：
3.3
作者：
Mohammad, Haroon;Mayhoub, Abdelrahman S.;Seleem, Mohamed N.
通讯作者：
Seleem, Mohamed N.