Herbicidins from <i>Streptomyces</i> sp. CB01388 Showing Anti-<i>Cryptosporidium</i> Activity

Chen, Jianjun; Rateb, Mostafa E.; Love, Melissa S.; Xu, Zhengren; Yang, Dong; Zhu, Xia; Huang, Yong; Zhao, Li‐Xing; Jiang, Yi; Duan, Yanwen; McNamara, Case W.; Shen, Ben

doi:10.1021/acs.jnatprod.7b00850

Cited by 11 publications

(13 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Five of the six herbicidins showed moderate anti-Cryptosporidium activity, with herbicidin K exhibiting comparable activity to the FDA-approved drug nitazoxanide. In addition, herbicidin K showed no toxicity to human cells, highlighting the promise of the herbicidin scaffold for anti-Cryptosporidium drug development (53). This final set of examples demonstrates the value of function-centric approaches, whereby previously characterized natural products can be connected with novel bioactivity.…”

Section: Function-centric Approachesmentioning

confidence: 78%

“…Upon subjecting the partially purified fraction collection of the NPL to our newly-developed imagebased assay, six herbicidins were discovered, one of which was new (Fig. 4D) (53). Five of the six herbicidins showed moderate anti-Cryptosporidium activity, with herbicidin K exhibiting comparable activity to the FDA-approved drug nitazoxanide.…”

Section: Function-centric Approachesmentioning

confidence: 99%

See 1 more Smart Citation

Leveraging a large microbial strain collection for natural product discovery

Steele

Teijaro

Yang

et al. 2019

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Section: Function-centric Approachesmentioning

confidence: 78%

Section: Function-centric Approachesmentioning

confidence: 99%

Leveraging a large microbial strain collection for natural product discovery

Steele

Teijaro

Yang

et al. 2019

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…Other potential compounds discovered from HTS campaigns with this HCI assay include TLR2/4 inhibitor oxidized phospholipid VB-201 and TrkA receptor antagonist ASP-7962 from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library, a drug repositioning collection of ~12,000 compounds (since expanded to >14,000). A small screen of fractions of natural products isolated from 159 microbial strains was performed as well, identifying five herbicidins with potent in vitro activity against C. parvum [70].…”

Section: Phenotypic-based Assays For Cryptosporidium Drug Discoverymentioning

confidence: 99%

Phenotypic screening techniques forCryptosporidiumdrug discovery

Love

McNamara

2020

Expert Opinion on Drug Discovery

Self Cite

View full text Add to dashboard Cite

Introduction: Two landmark epidemiological studies identified Cryptosporidium spp. as a significant cause of diarrheal disease in pediatric populations in resource-limited countries. Notably, nitazoxanide is the only approved drug for treatment of cryptosporidiosis but shows limited efficacy. As a result, many drug discovery efforts have commenced to find improved treatments. The unique biology of Cryptosporidium presents challenges for traditional drug discovery methods, which has inspired new assay platforms to study parasite biology and drug screening. Areas covered: The authors review historical advancements in phenotypic-based assays and techniques for Cryptosporidium drug discovery, as well as recent advances that will define future drug discovery. The reliance on phenotypic-based screens and repositioning of phenotypic hits from other pathogens has quickly created a robust pipeline of potential cryptosporidiosis therapeutics. The latest advances involve new in vitro culture methods for oocyst generation, continuous culturing capabilities, and more physiologically relevant assays for testing compounds. Expert opinion: Previous phenotypic screening techniques have laid the groundwork for recent cryptosporidiosis drug discovery efforts. The resulting improved methodologies characterize compound activity, identify, and validate drug targets, and prioritize new compounds for drug development. The most recent improvements in phenotypic assays are poised to help advance compounds into clinical development.

show abstract

“…L-9-10 [8], S. scopuliridis RB72 [9] and S. sp. CB01388 [10]. Herbicidins show selective herbicidal activity toward dicotyledonous plants [4], and also exhibit antialgal [7] and antifungal [6] activities.…”

Section: Introductionmentioning

confidence: 99%

“…Herbicidins show selective herbicidal activity toward dicotyledonous plants [4], and also exhibit antialgal [7] and antifungal [6] activities. Recently, a report highlights the herbicidin scaffold for anti- Cryptosporidium drug development [10]. The complex chemical structures and diverse biological activities have attracted our attention for further exploration of herbicidin congeners and their biosynthesis mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Exploring novel herbicidin analogues by transcriptional regulator overexpression and MS/MS molecular networking

Shi

et al. 2019

Microb Cell Fact

View full text Add to dashboard Cite

Background Herbicidin F has an undecose tricyclic furano-pyrano-pyran structure with post-decorations. It was detected from Streptomyces mobaraensis US-43 fermentation broth as a trace component by HPLC–MS analysis. As herbicidins exhibit herbicidal, antibacterial, antifungal and antiparasitic activities, we are attracted to explore more analogues for further development. Results The genome of S. mobaraensis US-43 was sequenced and a herbicidin biosynthetic gene cluster (hcd) was localized. The cluster contains structural genes, one transporter and three potential transcription regulatory genes. Overexpression of the three regulators respectively showed that only hcdR2 overexpression significantly improved the production of herbicidin F, and obviously increased the transcripts of 7 structural genes as well as the transporter gene. After performing homology searches using BLASTP in the GenBank database, 14 hcd-like clusters were found with a cluster-situated hcdR2 homologue. These HcdR2 orthologues showed overall structural similarity, especially in the C-terminal DNA binding domain. Based on bioinformatics analysis, a 21-bp consensus binding motif of HcdR2 was detected within 30 promoter regions in these genome-mined clusters. EMSA results verified that HcdR2 bound to the predicted consensus sequence. Additionally, we employed molecular networking to explore novel herbicidin analogues in hcdR2 overexpression strain. As a result, ten herbicidin analogues including six new compounds were identified based on MS/MS fragments. Herbicidin O was further purified and confirmed by 1H NMR spectrum. Conclusions A herbicidin biosynthetic gene cluster (hcd) was identified in S. mobaraensis US-43. HcdR2, a member of LuxR family, was identified as the pathway-specific positive regulator, and the production of herbicidin F was dramatically increased by overexpression of hcdR2. Combined with molecular networking, ten herbicidin congeners including six novel herbicidin analogues were picked out from the secondary metabolites of hcdR2 overexpression strain. The orthologues of herbicidin F pathway-specific regulator HcdR2 were present in most of the genome-mined homologous biosynthetic gene clusters, which possessed at least one consensus binding motif with LuxR family characteristic. These results indicated that the combination of overexpression of hcdR2 orthologous regulator and molecular networking might be an effective way to exploit the “cryptic” herbicidin-related biosynthetic gene clusters for discovery of novel herbicidin analogues.

show abstract

Herbicidins from Streptomyces sp. CB01388 Showing Anti-Cryptosporidium Activity

Cited by 11 publications

References 52 publications

Leveraging a large microbial strain collection for natural product discovery

Leveraging a large microbial strain collection for natural product discovery

Phenotypic screening techniques forCryptosporidiumdrug discovery

Exploring novel herbicidin analogues by transcriptional regulator overexpression and MS/MS molecular networking

Contact Info

Product

Resources

About