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1. (WO2019027877) CRYPTIC METABOLITES AND METHOD FOR ACTIVATING SILENT BIOSYNTHETIC GENE CLUSTERS IN DIVERSE MICROORGANISMS
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Pub. No.: WO/2019/027877 International Application No.: PCT/US2018/044328
Publication Date: 07.02.2019 International Filing Date: 30.07.2018
IPC:
C12N 1/20 (2006.01) ,C12N 1/38 (2006.01) ,C12Q 1/02 (2006.01) ,G01N 33/68 (2006.01)
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
1
Micro-organisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving micro-organisms or compositions thereof; Processes of preparing or isolating a composition containing a micro-organism; Culture media therefor
20
Bacteria; Culture media therefor
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
1
Micro-organisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving micro-organisms or compositions thereof; Processes of preparing or isolating a composition containing a micro-organism; Culture media therefor
38
Chemical stimulation of growth or activity by addition of chemical compounds which are not essential growth factors; Stimulation of growth by removal of a chemical compound
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
Q
MEASURING OR TESTING PROCESSES INVOLVING ENZYMES OR MICRO-ORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
1
Measuring or testing processes involving enzymes or micro-organisms; Compositions therefor; Processes of preparing such compositions
02
involving viable micro-organisms
G PHYSICS
01
MEASURING; TESTING
N
INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
33
Investigating or analysing materials by specific methods not covered by groups G01N1/-G01N31/131
48
Biological material, e.g. blood, urine; Haemocytometers
50
Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
68
involving proteins, peptides or amino acids
Applicants:
THE TRUSTEES OF PRINCETON UNIVERSITY [US/US]; 87 Prospect Avenue Princeton, NJ 08544, US
Inventors:
SEYEDSAYAMDOST, Mohammad R.; US
XU, Fei; US
WU, Yihan; US
BUSHIN, Leah; US
DAVIS, Katherine; US
Agent:
PATTILLO, Alan C.; US
Priority Data:
62/539,26331.07.2017US
Title (EN) CRYPTIC METABOLITES AND METHOD FOR ACTIVATING SILENT BIOSYNTHETIC GENE CLUSTERS IN DIVERSE MICROORGANISMS
(FR) MÉTABOLITES CRYPTIQUES ET PROCÉDÉ D'ACTIVATION DE GROUPES DE GÈNES BIOSYNTHÉTIQUES SILENCIEUX DANS DIVERS MICRO-ORGANISMES
Abstract:
(EN) Microorganisms are prolific producers of natural products, a group of molecules that make up the majority of drugs approved by the FDA in the past 35 years. After decades of mining, the low-hanging fruit has been picked and so discovery of drug-like molecules from microorganisms has come to a near-halt. The reason for this lack of productivity is that most biosynthetic pathways that give rise to natural products are not active under typical laboratory growth conditions. These so-called 'cryptic' or 'silent' pathways are a major source of new bioactive molecules and methods that reliably activate them could have a profound impact on drug discovery. 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.
(FR) Les micro-organismes sont des producteurs prolifiques de produits naturels, un groupe de molécules qui constituent la majorité des médicaments approuvés par la FDA au cours des 35 dernières années. Après des décennies de prospection, les fruits à portée de main ont été cueillis et la découverte de molécules de type médicament provenant de micro-organismes s'est donc quasiment arrêtée. La raison de ce manque de productivité est que la plupart des voies de biosynthèse qui donnent naissance à des produits naturels ne sont pas actives dans des conditions caractéristiques de croissance en laboratoire. Ces voies dites 'cryptiques' ou 'silencieuses' sont une source majeure de nouvelles molécules bioactives et des procédés qui les activent de manière fiable pourraient avoir un impact important sur la découverte de médicaments. L'invention concerne un procédé rapide sans génétique pour déclencher et détecter des métabolites cryptiques à l'aide d'une approche basée sur l'imagerie par spectrométrie de masse. Un organisme de choix est confronté à des éliciteurs provenant d'une bibliothèque de petites molécules. Les molécules élicitées sont ensuite représentées par imagerie par spectrométrie de masse, ce qui permet une identification rapide de métabolites cryptiques. Ceux-ci sont ensuite isolés et caractérisés. L'utilisation de l'approche divulguée a activé la production de glycopeptides cryptiques provenant d'une bactérie d'actinomycète. Les molécules qui en résultent, les kératinimicines et les kératinicyclines sont des métabolites pourvus de caractéristiques structurales importantes. Au moins deux de ceux-ci, des kératinimicines B et C, sont hautement bioactifs vis-à-vis de plusieurs souches pathogènes. Cette approche permettra une activation et une identification rapides de métabolites cryptiques provenant de divers micro-organismes dans le futur.
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Designated States: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Office (AM, AZ, BY, KG, KZ, RU, TJ, TM)
European Patent Office (EPO) (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG)
Publication Language: English (EN)
Filing Language: English (EN)