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1. 发明申请

US20200297669A1 GUANFACINE AS AN ANTI-VIRULENCE AGENT 审中-公开
公开(公告)号：US20200297669A1
公开(公告)日：2020-09-24
申请号：US16824968
申请日：2020-03-20
申请人： The Trustees of Princeton University
发明人： Mohammad R. Seyedsayamdost , Bethany K. Okada , Anran Li
IPC分类号： A61K31/155 , A61P31/04
摘要： Disclosed are methods for using guanfacine, an analog or derivative of guanfacine, or a pharmaceutically acceptable salt thereof, to reduce the virulence of a bacterial pathogen. When treating a patient, the method generally involves administering to the patient a therapeutically effective dose of guanfacine, an analog or derivative of guanfacine, or a pharmaceutically acceptable salt thereof. An alternative method involves contacting the bacterial pathogen with guanfacine, an analog or derivative of guanfacine, or a pharmaceutically acceptable salt thereof.

2. 发明申请

US20210156840A1 CRYPTIC ANTIBIOTICS AND METHODS FOR DETECTING BIOACTIVE CRYPTIC METABOLITES 有权
公开(公告)号：US20210156840A1
公开(公告)日：2021-05-27
申请号：US17100005
申请日：2020-11-20
申请人： THE TRUSTEES OF PRINCETON UNIVERSITY
发明人： Mohammad R. Seyedsayamdost , Kyuho Moon
IPC分类号： G01N33/483 , C12N1/20
摘要： Bacteria harbor an immense reservoir of potentially new and therapeutic small molecules in the form of “silent” biosynthetic gene clusters. These clusters can be identified bioinformatically but are at best sparingly expressed under normal laboratory growth conditions; their products are therefore not interrogated during bioactivity screening exercises. An estimated 80-90% of biosynthetic loci are silent, meaning that routine bioactivity screens miss the majority of microbial biosynthetic potential. Disclosed herein is a method that allows access to this vast hidden metabolome, thereby allowing researchers to screen the complete metabolomes of microorganisms in the search of new therapeutic leads. The disclosed approach, “Bioactivity-HiTES”, broadly activates the secondary metabolomes of bacteria and links the cryptic metabolites produced to a desired biological activity. Using the disclosed method, induction of cryptic antibiotics was detected in all four actinomycete bacterial strains that were tested as proof-of-concept. Follow-up in two cases demonstrated the production of two new antibiotics: In one case, the taylorflavins, pyrimidine antibiotics that harbor selective growth-inhibitory activity toward Gram-negative bacteria, were identified. For example, taylorflavin B shows potent minimal inhibitory concentration toward Neisseria gonorrhoeae and Acinetobacter baumanii, but not against a panel of Gram-positive bacteria. In the second case, the lanthipeptide cebulantin, which is specific toward Gram-negative Vibrio pathogens, but does not affect the growth of Gram-positive bacteria tested, was identified. These compounds, taylorflavins and cebulantin, may serve as useful leads in the future. At the same time, Bioactivity-HiTES may be applied broadly to identify cryptic metabolites with the desired biological properties.

3. 发明申请

US20180355397A1 Method for Awakening Silent Gene Clusters in Bacteria and Discovery of Cryptic Metabolites 审中-公开
公开(公告)号：US20180355397A1
公开(公告)日：2018-12-13
申请号：US16104319
申请日：2018-08-17
申请人： The Trustees of Princeton University
发明人： Mohammad R. Seyedsayamdost
IPC分类号： C12Q1/02 , C12N15/52 , C12P17/06
CPC分类号： C12Q1/025 , C12N15/52 , C12P17/06
摘要： The majority of clinically used antibiotics and anticancer agents are derived from bacterial small molecules. These molecules are produced by dedicated biosynthetic gene clusters, sets of genes that are responsible for the step-wise generation of the target small molecule. Recent investigations have indicated, to the surprise of many experts, that the majority of these biosynthetic genes are inactive or ‘silent’ for unknown reasons. Thus under typical bacterial culturing conditions, these genes are not expressed and consequently the bioactive small molecule products are not synthesized. Disclosed is a method for high throughput screening of elicitors of cryptic metabolites, a method for producing cryptic metabolites, and a new family of cryptic metabolites, the acybolins, as well as their complete structural elucidation.

4. 发明授权

US11813235B2 Guanfacine as an anti-virulence agent 有权
公开(公告)号：US11813235B2
公开(公告)日：2023-11-14
申请号：US16824968
申请日：2020-03-20
申请人： The Trustees of Princeton University
发明人： Mohammad R. Seyedsayamdost , Bethany K. Okada , Anran Li
IPC分类号： A61K31/155 , A61P31/04 , A61K45/06
CPC分类号： A61K31/155 , A61P31/04 , A61K45/06
摘要： Disclosed are methods for using guanfacine, an analog or derivative of guanfacine, or a pharmaceutically acceptable salt thereof, to reduce the virulence of a bacterial pathogen. When treating a patient, the method generally involves administering to the patient a therapeutically effective dose of guanfacine, an analog or derivative of guanfacine, or a pharmaceutically acceptable salt thereof. An alternative method involves contacting the bacterial pathogen with guanfacine, an analog or derivative of guanfacine, or a pharmaceutically acceptable salt thereof.

5. 发明申请

US20230044467A1 GLYCOPEPTIDE ANTIBIOTIC COMBINATION THERAPY 有权
公开(公告)号：US20230044467A1
公开(公告)日：2023-02-09
申请号：US17873269
申请日：2022-07-26
申请人： The Trustees of Princeton University
发明人： Mohammad R. Seyedsayamdost , Vasiliki T. Chioti , Katherine M. Davis , Kirklin L. McWhorter
IPC分类号： A61K38/14 , C07K9/00 , A61P31/04
摘要： Bacterial infections evading the current antibiotic arsenal warrant new treatment options. The mainstay treatment for Clostridium difficile infections involves administration of the broad-spectrum antibiotic vancomycin, which also depletes the gut microbiome and its natural defenses. This leads to recurrent C. difficile infections in 20-30% of patients. Alternative treatment options are limited, triggering a perpetual cycle of relapse and recovery that may eventually lead to death. Keratinicyclin B represents a glycopeptide antibiotic chemotype with a mechanism of action that is selective for Clostridia. When combined, vancomycin (or other glycopeptide antibiotic) and keratinicyclin B interact synergistically to inhibit the growth of C. difficile at concentrations far lower than their respective minimal inhibitory concentrations. Such a combination therapy could allow for targeted colonization clearance at low antibiotic doses, thereby minimizing toxicity and reducing the likelihood of relapse.

6. 发明授权

US10941434B2 Method for awakening silent gene clusters in bacteria and discovery of cryptic metabolites 有权
公开(公告)号：US10941434B2
公开(公告)日：2021-03-09
申请号：US16104319
申请日：2018-08-17
申请人： The Trustees of Princeton University
发明人： Mohammad R. Seyedsayamdost
IPC分类号： C40B30/06 , C12Q1/02 , C12N15/52 , C12P17/06
摘要： The majority of clinically used antibiotics and anticancer agents are derived from bacterial small molecules. These molecules are produced by dedicated biosynthetic gene clusters, sets of genes that are responsible for the step-wise generation of the target small molecule. Recent investigations have indicated, to the surprise of many experts, that the majority of these biosynthetic genes are inactive or ‘silent’ for unknown reasons. Thus under typical bacterial culturing conditions, these genes are not expressed and consequently the bioactive small molecule products are not synthesized. Disclosed is a method for high throughput screening of elicitors of cryptic metabolites, a method for producing cryptic metabolites, and a new family of cryptic metabolites, the acybolins, as well as their complete structural elucidation.

7. 发明授权

US11629174B2 Cryptic metabolites and method for activating silent biosynthetic gene clusters in actinomycete bacteria 有权
公开(公告)号：US11629174B2
公开(公告)日：2023-04-18
申请号：US16610330
申请日：2018-05-11
申请人： The Trustees of Princeton University
发明人： Mohammad R. Seyedsayamdost , Fei Xu , Kyuho Moon , Behnam Nazari
IPC分类号： C07K14/36 , C07K7/64 , C12N1/20 , C12N1/38 , G01N33/50 , C12Q1/02 , A61K38/00
摘要： Disclosed is a high-throughput transcriptional assay format in Actinomycete bacteria, and Streptomyces spp. in particular, that leverages eGFP, inserted both at a neutral site and inside the biosynthetic cluster of interest, as a read-out for secondary metabolite synthesis. Using this approach, a silent gene cluster in Streptomyces albus J1074 was induced. The cytotoxins etoposide and ivermectin were revealed as potent inducers, allowing the isolation and structural characterization of nearly 20 novel small molecule products of the chosen cluster. One of these molecules is a novel antifungal, while several others inhibit a cysteine protease implicated in cancer. Studies addressing the mechanism of induction by the two elicitors led to the identification of a pathway-specific transcriptional repressor that silences the gene cluster under normal growth conditions. The successful implementation of this approach will allow future discovery of cryptic metabolites with useful bioactivities from Actinomycete bacteria.

8. 发明授权

US11549950B2 Cryptic metabolites and method for activating silent biosynthetic gene clusters in diverse microorganisms 有权
公开(公告)号：US11549950B2
公开(公告)日：2023-01-10
申请号：US16634388
申请日：2018-07-30
申请人： The Trustees of Princeton University
发明人： Mohammad R. Seyedsayamdost , Fei Xu , Yihan Wu , Leah Bushin , Katherine Davis
IPC分类号： G01N33/68 , C07K9/00 , C12N1/20 , C12N1/38 , C12P19/56 , C12P21/00 , C12Q1/18
摘要： Disclosed herein is a rapid genetics-free method for eliciting and detecting cryptic metabolites using an imaging mass spectrometry-based approach. An organism of choice is challenged with elicitors from a small molecule library. The molecules elicited are then imaged by mass spec, which allows for rapid identification of cryptic metabolites. These are then isolated and characterized. Employing the disclosed approach activated production of cryptic glycopeptides from an actinomycete bacterium. The molecules that result, the keratinimicins and keratinicyclins, are metabolites with important structural features. At least two of these, keratinimicins B and C, are highly bioactive against several pathogenic strains. This approach will allow for rapid activation and identification of cryptic metabolites from diverse microorganisms in the future.

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