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WO1991006674A1 - Procede et dispositif de detection de la resistance aux antibiotiques - Google Patents

Procede et dispositif de detection de la resistance aux antibiotiques Download PDF

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Publication number
WO1991006674A1
WO1991006674A1 PCT/GB1990/001697 GB9001697W WO9106674A1 WO 1991006674 A1 WO1991006674 A1 WO 1991006674A1 GB 9001697 W GB9001697 W GB 9001697W WO 9106674 A1 WO9106674 A1 WO 9106674A1
Authority
WO
WIPO (PCT)
Prior art keywords
probe
support
antibiotic resistance
probes
nucleic acid
Prior art date
Application number
PCT/GB1990/001697
Other languages
English (en)
Inventor
William Joseph Harris
Francis Joseph Carr
Original Assignee
Scotgen Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scotgen Ltd. filed Critical Scotgen Ltd.
Publication of WO1991006674A1 publication Critical patent/WO1991006674A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C12Q1/689—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria

Definitions

  • the invention relates to a method of detecting antibiotic resistance, in particular in bacteria; to a kit for use in such a method; and to components usable in such a method.
  • Antibiotics may be used in the treatment of infections caused by, for example, pathogenic bacteria. Examples of such infections are urinary tract infections (UTI).
  • UTI urinary tract infections
  • the incidence of UTIs worldwide is second only to upper respiratory tract infections although the frequency of testing of UTI far exceeds that for respiratory pathogens.
  • the major activity of clinical bacteriology laboratories is in testing urine samples for the presence of bacterial pathogens and, subsequently, for the resistance of those pathogens bacteria to antibiotics, thus guiding the clinician in the choice of antibiotics for UTI therapy.
  • Trimethoprin altered target enzyme (dihydrofolate reductase)
  • E.coli is the organism predominantly isolated from such samples, and has been reported in over 80% of cases of significant bacteriuria (Mond et al ig65; Lancet, i., 514-416; Trepeta and Edberg, ig84, J Clin Microbial 1 No 2, 172-174).
  • Many new methods of detection are based upon the detection of enzymes characteristic for the bacteria, in particular detection of the enzymes ⁇ -galactosidase and f?
  • a method for detecting antibiotic resistance in a sample which comprises providing a support, a first probe capable of specifically binding to part of the nucleic acid encoding the antibiotic resistance, means being provided whereby the probe is immobilisable on said support, and a second probe capable of specifically binding another part of the nucleic acid encoding the antibiotic resistance, the second probe being labelled so as to be capable of producing a signal; allowing nucleic acid from the sample to come into contact with the first probe and the labelled second probe; immobilising the first probe on the support; and detecting any signal from labelled second probe bound to the support by cohybridisation of the immobilised first probe and the labelled probe to antibiotic resistance nucleic acid.
  • the probes may be oligonucleotide probes, isolated gene segments or corresponding RNA.
  • the nucleic acid encoding resistance may be RNA or DNA.
  • the first probe may be immobilised on the support before it interacts with the target nucleic acid. Alternatively the immobilisation may happen during and/or after such interaction.
  • FITC and nitroindophenol can be incorporated by reaction of a succimidyl derivative with a 5' amino group on the oligonucleotide.
  • Dinitrophenol can be attached via dinitrobenzene sulphonic acid.
  • Penicillin can be attached via penicillinic acid.
  • the DNA probes are specific to genes encoding resistance to: penicillins/cephalosporins; trimethoprim; aminoglycosides; or tetracycline.
  • the method is suitable for the detection of bacterial antibiotic resistance in a clinical sample, such as urine.
  • Bacterial DNA from the sample is suitably prepared by lysing the bacteria with an alkaline buffer and denaturing the DNA.
  • the labelled probe may then be added with a neutralising buffer.
  • the label may be an enzyme, and a suitable signal producing system is one which produces a colour in the presence of the product resulting from the action on the enzyme on a suitable substrate.
  • the method provides for the simultaneous detection of different classes of antibiotic resistances by providing distinct regions of a first set of probes on the support and a second set of labelled probes which are specific for antibiotic resistance genes of each of the classes.
  • the support may be in the form of a dipstick to which said first set of probes are attached in separate discrete areas.
  • the dipstick may be made of paper, nylon, plastics or any other suitable material.
  • the support may be in the form of a multiwell microtitration plate, with probes of the first set immobilised in separate wells.
  • Figure 1 shows diagrammatically a dipstick with four regions for detecting antibiotic resistance
  • Figure 2 shows diagrammatically a multiwell format alternative to the dipstick of Figure 1.
  • a dipstick 10 for example of plastic, nylon, paper or other suitable material, having thereon four separate strips A-D.
  • Each of the strips comprises a DNA probe, for example an oligonucleotide probe, specific for genes conferring resistance to different antibiotics: strip A - penicillin strip B - trimethoprim strip C - aminoglycosides strip D - tetracycline
  • Each DNA probe is attached to the dipstick by conventional procedures, such as chemical covalent linkage of the 3' -OH end, or through ligand-mediated processes, or any other suitable process.
  • a small volume of urine is treated with an alkaline buffer to lyse bacteria and denature the DNA therein.
  • a neutralising buffer is added which contains a set of DNA probes, e.g. oligonucleotide probes, specific for each of the four antibiotic resistance genes, these probes being labelled with enzyme, e.g. alkaline phosphatase.
  • the lengths of the probes are 15 chosen so as to provide sufficient specificity and stability during hybridisation.
  • the DNA of each probe immobilised on the dipstick should hybridise to a different region of the antibiotic resistance gene from the corresponding labelled probe, so that both can simultaneously hybridise to the 20 bacterial DNA.
  • a multiwell plate 12 for example a conventional 12 x 8 well microtitre plate, in which the first set of DNA probes are attached to separate wells or groups of wells A-D by conventional methods.
  • I 25 Urine samples, treated and exposed to a set of labelled probes as described above, are distributed between the wells of the plate, and after hybridisation the wells are washed before the addition of enzyme substrate for colour development.
  • the result will be a profile of antibiotic resistance, for example as depicted in Figure 2.
  • Fig. 2 indicates, using a multiwell assay it is possible to test several different test samples at the same time by introducing them in rows on the plate.
  • RNA probes could be used instead of DNA probes.
  • the number of different antibiotic resistances tested may also vary.
  • This example describes the preparation of dipsticks and their use to detect and discriminate between two plasmid DNA sequences encoding resistance to the antibiotics tetracycline and kanamycin.
  • both probes are initially in solution but one beomes immobilised by interaction with an antibody associated with a dipstick.
  • all antibodies, plasmids and other reagents were obtained from Sigma Chemical Co., Poole, Dorset, England. 5 1 * Purification of antibodies
  • Sheets of nitrocellulose membrane (Sartorius), pore size 0.45 ⁇ m, were prewetted with tris/saline (lOmM tris, 0.9% (w/v) sodium chloride, pH7.4) and placed in a "Bio-Slot" apparatus 15 (BioRad).
  • a ligand binding moiety "was provided in the form of an antibody to BuDR.
  • l ⁇ g of purified antibody in 200 ⁇ l tris/saline was placed in each well and allowed to pass through the membrane. After half an hour, the wells were washed with 200ul tris/saline. The membrane was removed and 20 stored at 4°C in tris/saline containing 5% (w/v) bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • probes can be labelled with FITC as follows. 20 ⁇ g of 5'-amino-oligonucleotide was mixed with 20 ⁇ l FITC (4mg/ml in N,N'-dimethylformamide), 30 ⁇ l of IM carbonate/bicarbonate buffer, pH9.0, and distilled water to a final volume of 150 ⁇ l. This reaction mixture was incubated overnight at room temperature in the dark, then extracted five times with ethyl acetate to remove free FITC.
  • the dried material was rehydrated with 200 ⁇ l O.IM carbonate/bicarbonate, pH8.25, containing 3M sodium chloride, 0.05% (w/v) sodium azide and 1 mg alkaline phosphatase. After 16 hours at room temperature, the reaction products were separated by gel filtration using a Zorbax GF250 column equilibrated with 0.2M sodium phosphate, pH7.0. The conjugated reporter probe is the first peak to emerge.
  • Strips (5cm x 1cm) cut from the membranes produced as described in section 2 above were prehybridized for 1 hour at 37C in 5 ml of 4XSSC (0.6M sodium chloride, 0.06M sodium citrate, pH7.0), 10% (v/v) deionized formamide, 5% (w/v) BSA and 0.1 mg/ml heat-denatured sheared salmon sperm DNA.
  • plasmids pBR322 and pUBHO O.l ⁇ g

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Procédé permettant une détection rapide et aisée de la résistance aux antibiotiques dans un échantillon, et un kit mettant en ÷uvre ledit procédé. Le procédé consiste à prévoir un support, ainsi qu'une première sonde capable de se lier spécifiquement à une partie de l'acide nucléique codant pour la résistance aux antibiotiques, et qui peut être immobilisée sur le support avant et pendant la séquence d'essais. On prévoit également une deuxieme sonde capable de se lier spécifiquement à une autre partie de l'acide nucléique codant pour la résistance aux antibiotiques, cette deuxième sonde pouvant être étiquetée de manière à pouvoir émettre un signal. On fait en sorte que l'acide nucléique provenant de l'échantillon se mette en contact avec la première sonde et la deuxième sonde étiquetée. On détecte tout signal provenant de la deuxième sonde étiquetée liée au support par cohybridation de la première sonde immobilisée et de la sonde étiquetée avec l'acide nucléique codant pour la résistance aux antibiotiques.
PCT/GB1990/001697 1989-11-06 1990-11-06 Procede et dispositif de detection de la resistance aux antibiotiques WO1991006674A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898924989A GB8924989D0 (en) 1989-11-06 1989-11-06 Method and device for the detection of antibiotic resistance
GB8924989.0 1989-11-06

Publications (1)

Publication Number Publication Date
WO1991006674A1 true WO1991006674A1 (fr) 1991-05-16

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993022454A1 (fr) * 1992-04-30 1993-11-11 Institut Pasteur Detection rapide de la resistance aux antibiotiques de mycobacterium tuberculosis
FR2704002A1 (fr) * 1993-04-16 1994-10-21 Pasteur Institut Méthode de détection de la résistance des mycobactéries à la streptomycine, kit de diagnostic pour la mise en Óoeuvre et séquence nucléotidique du gène rpsL de mycobacterium tuberculosis.
US5851763A (en) * 1992-09-17 1998-12-22 Institut Pasteur Rapid detection of antibiotic resistance in mycobacterium tuberculosis
US6124098A (en) * 1992-04-30 2000-09-26 Institut Pasteur Rapid detection of antibiotic resistance in mycobacterium tuberculosis
EP0905258A3 (fr) * 1992-11-27 2001-01-31 Innogenetics N.V. Procédé pour la détection de séquences d'acides nucléiques utilisant de sondes nucléotidiques immobilisées en phase solide (line probe assay)
EP1674583A1 (fr) * 2004-12-23 2006-06-28 Eppendorf Array Technologies SA Procédé et trousse permettant la détection de plusieurs gènes de résistance aux antibiotiques dans des micro-organismes
US7196183B2 (en) 2001-08-31 2007-03-27 Innogenetics N.V. Hepatitis C virus genotype, and its use as prophylactic, therapeutic and diagnostic agent
US8124747B2 (en) 2003-08-29 2012-02-28 Innogenetics HCV clade and prototype sequences thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1983001459A1 (fr) * 1981-10-16 1983-04-28 Ranki, Tuula, Marjut Procede et combinaison d'agents de reaction pour le diagnostic de micro-organismes par hybridation en sandwich d'acides nucleiques
EP0139489A2 (fr) * 1983-09-26 1985-05-02 Ortho Diagnostic Systems Inc. Méthode d'hybridation en sandwich pour la détection d'acides nucléiques
GB2169403A (en) * 1985-01-02 1986-07-09 Orion Yhtymae Oy Identification of nucleic acids
EP0231010A2 (fr) * 1986-01-27 1987-08-05 INCSTAR Corporation Procédé pour un essai immuno-enzymique en phase solide et essai d'hybridisation des acides nucléiques et dessin d'un bâtonnet d'échantillon et substrat chromogène stabilisé
WO1988006189A1 (fr) * 1987-02-12 1988-08-25 Sdi Diagnostics, Inc. Systeme de test, dispositif de test et procede servant a detecter la presence d'organismes pathogenes et de genes resistants aux antibiotiques dans des echantillons
EP0300923A2 (fr) * 1987-07-24 1989-01-25 Universite Laval Sonde d'ADN pour déterminer la production de beta-lactamase dans des bactéries gramnégatives
EP0317077A1 (fr) * 1987-10-15 1989-05-14 Chiron Corporation Multimères d'acides nucléiques et essais d'hybridations amplifiées d'acides nucléiques les utilisant
EP0225807B1 (fr) * 1985-12-11 1994-10-19 Chiron Corporation Essai de l'acide nucléique en phase solution et les sondes polynucléotidiques convenant pour cela

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1983001459A1 (fr) * 1981-10-16 1983-04-28 Ranki, Tuula, Marjut Procede et combinaison d'agents de reaction pour le diagnostic de micro-organismes par hybridation en sandwich d'acides nucleiques
EP0139489A2 (fr) * 1983-09-26 1985-05-02 Ortho Diagnostic Systems Inc. Méthode d'hybridation en sandwich pour la détection d'acides nucléiques
GB2169403A (en) * 1985-01-02 1986-07-09 Orion Yhtymae Oy Identification of nucleic acids
EP0225807B1 (fr) * 1985-12-11 1994-10-19 Chiron Corporation Essai de l'acide nucléique en phase solution et les sondes polynucléotidiques convenant pour cela
EP0231010A2 (fr) * 1986-01-27 1987-08-05 INCSTAR Corporation Procédé pour un essai immuno-enzymique en phase solide et essai d'hybridisation des acides nucléiques et dessin d'un bâtonnet d'échantillon et substrat chromogène stabilisé
WO1988006189A1 (fr) * 1987-02-12 1988-08-25 Sdi Diagnostics, Inc. Systeme de test, dispositif de test et procede servant a detecter la presence d'organismes pathogenes et de genes resistants aux antibiotiques dans des echantillons
EP0300923A2 (fr) * 1987-07-24 1989-01-25 Universite Laval Sonde d'ADN pour déterminer la production de beta-lactamase dans des bactéries gramnégatives
EP0317077A1 (fr) * 1987-10-15 1989-05-14 Chiron Corporation Multimères d'acides nucléiques et essais d'hybridations amplifiées d'acides nucléiques les utilisant

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993022454A1 (fr) * 1992-04-30 1993-11-11 Institut Pasteur Detection rapide de la resistance aux antibiotiques de mycobacterium tuberculosis
US6124098A (en) * 1992-04-30 2000-09-26 Institut Pasteur Rapid detection of antibiotic resistance in mycobacterium tuberculosis
US5851763A (en) * 1992-09-17 1998-12-22 Institut Pasteur Rapid detection of antibiotic resistance in mycobacterium tuberculosis
EP0905258A3 (fr) * 1992-11-27 2001-01-31 Innogenetics N.V. Procédé pour la détection de séquences d'acides nucléiques utilisant de sondes nucléotidiques immobilisées en phase solide (line probe assay)
FR2704002A1 (fr) * 1993-04-16 1994-10-21 Pasteur Institut Méthode de détection de la résistance des mycobactéries à la streptomycine, kit de diagnostic pour la mise en Óoeuvre et séquence nucléotidique du gène rpsL de mycobacterium tuberculosis.
US7196183B2 (en) 2001-08-31 2007-03-27 Innogenetics N.V. Hepatitis C virus genotype, and its use as prophylactic, therapeutic and diagnostic agent
US8124747B2 (en) 2003-08-29 2012-02-28 Innogenetics HCV clade and prototype sequences thereof
EP1674583A1 (fr) * 2004-12-23 2006-06-28 Eppendorf Array Technologies SA Procédé et trousse permettant la détection de plusieurs gènes de résistance aux antibiotiques dans des micro-organismes
WO2006066369A2 (fr) * 2004-12-23 2006-06-29 Eppendorf Array Technologies S.A. Procede et kit d'identification et/ou de detection et/ou de quantification d'un nombre eleve de genes relatifs a la resistance antibiotique dans les (micro)organismes
WO2006066369A3 (fr) * 2004-12-23 2007-02-08 Eppendorf Array Tech Sa Procede et kit d'identification et/ou de detection et/ou de quantification d'un nombre eleve de genes relatifs a la resistance antibiotique dans les (micro)organismes

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Publication number Publication date
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