WO2002000165A2 - Agents permettant d'inverser la resistance aux medicaments de mycobacterium tuberculosis - Google Patents

Agents permettant d'inverser la resistance aux medicaments de mycobacterium tuberculosis Download PDF

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Publication number
WO2002000165A2
WO2002000165A2 PCT/IB2001/001136 IB0101136W WO0200165A2 WO 2002000165 A2 WO2002000165 A2 WO 2002000165A2 IB 0101136 W IB0101136 W IB 0101136W WO 0200165 A2 WO0200165 A2 WO 0200165A2
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WO
WIPO (PCT)
Prior art keywords
inh
resistance
penicillin
tuberculosis
penicillins
Prior art date
Application number
PCT/IB2001/001136
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English (en)
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WO2002000165A3 (fr
Original Assignee
Bakulesh Mafatlal, Khamar
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 Bakulesh Mafatlal, Khamar filed Critical Bakulesh Mafatlal, Khamar
Priority to AU66257/01A priority Critical patent/AU6625701A/en
Priority to APAP/P/2002/002454A priority patent/AP2002002454A0/en
Priority to EA200200290A priority patent/EA004875B1/ru
Publication of WO2002000165A2 publication Critical patent/WO2002000165A2/fr
Publication of WO2002000165A3 publication Critical patent/WO2002000165A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention provides agents for reversal of INH resistance in Mycobacterium tuberculosis.
  • penicillins reverses resistances of Mycobacterium to INH.
  • Isoniazid is the most widely used anti-tuberculous drug. It is one of the main therapeutic agent.
  • the strains of mycobacterium are usually inhibited at the concentration of 0.2 mcg/ml or less. When a particular strain is not inhibited by INH concentration of 1.0 mcg/ml, it is labeled as resistant strain.
  • Inh-A NADH-dependent en . ocyl acyl carrier protein reductase is the primary target for this drug (Miesel L et al., 1998).
  • a reactive form of isoniazid inhibits inh-A by reacting with the NADH cofactor to the enzyme active site forming a covalent adduct (isonicotinic acyl NADH) that is apt to bind with high affinity.
  • Ndh NADH dehydrogenase
  • INH resistant tuberculosis including multidrug resistant tuberculosis drugs like ciprofloxacin, Kanamycin, Pr ⁇ thionamide etc. are used along with other primary drugs.
  • the management of resistant infection involve use of drugs to which organisms are sensitive.
  • Penicillin is the oldest antibiotic available and in use even to-day. It has been evaluated for management of various infections including mycobacterial infections (US Public Health Service General Research Support, 1973). Use of penicillin alone had not been found to be therapeutically effective in the treatment of tuberculosis. MIC of penicillins against mycobacterium is significantly high. It is not possible to achieve therapeutic concentration of penicillins required to treat infection effectively,
  • beta-lactamase inhibitors The attempts have been made to overcome this problem by combining penicillins with beta-lactamase inhibitors.
  • MIC of ampicillin alone was 32 mcg/ml, but when combined with Clavulanic acid it was 4 meg /ml.
  • Ciprofloxacin has been used in newly diagnosed cases of pulmonary tuberculosis (Frederick A et al., 1997). However, emergence of resistance to ciprofloxacin against MDR strains has aroused concern (Fattorini L ae tal., 1999).
  • Sacchettini JC Blanchard JS. The structure and function of of the isoniazid target in M. tuberculosis.
  • Wilson TM Collins DM. ahpC, a gene involved in isoniazid resistance of the Mycobacterium tuberculosis complex.
  • Banerjee A et al. inhA a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis.
  • Yuan Y et al. The effect of oxygenated mycolic acid composition on cell wall function and macrophage growth in Mycobacterium tuberculosis.
  • the present invention overcomes the problem of INH resistance by penicillins.
  • penicillins are found to cause reduction in MIC of INH against multi-drug resistant strains of Mycobacterium tuberculosis, and making them sensitive to INH.
  • the strains of mycobacterium not inhibited by INH at concentration of 1.0 mcg/ml by agar plate method gets inhibited by INH when 1.0 to 2.0 mcg/ml of penicillins is added to it.
  • the present invention uses penicillins to overcome the problem of INH resistance. This has been done by using penicillins in combination with INH.
  • Penicillins on its own does not have activity against M. tuberculosis at a dose used or can be used. But when it is combined with INH, it improves sensitivity profile (MIC) of INH.
  • the strains which are resistant to INH becomes sensitive to INH. The strain is known as resistant if it is not inhibited at 1.0 mcg/ml. For the purpose of demonstrating reversal of mycobacterial resistance to INH, an agar plate method has been used.
  • Ten strains (clinical isolates) of M. tuberculosis with various sensitive and resistant patterns to first-line anti-tuberculous drugs were evaluated using varying concentrations of INH (0.1 , 0.2 andl .O) and Cloxacillin ( 0.25, 0.5, 1.0 and 2.0) combination and MIC were determined for each group.
  • One group had INH 0.2 and Cloxacillin and in this, 4 concentrations using 0.25, 0.5, 1.0 and 2.0 were used to determine MIC.
  • INH 0.2 and Cloxacillin was used and this as well, 4 concentrations (0.25, 0.5, 1.0 and 2.0) were used to determine MIC.
  • INH 1.0 and Cloxacillin were taken and again similar 4 concentrations were used. So in each group, 4 LJ bottles for each M. tuberculosis strain was used. For one strain, in all, 12 bottles were used to determine MIC. The experiments were repeated more than once for consistency.
  • the findings reveal that strains resistant to INH at more than 1.0 mcg/ml becomes sensitive to INH at 0.1 mcg/ml, when Cloxacillin 2.0 mcg/ml is used along with it. All strains become sensitive to INH 1.0 mcg/ml in presence of 1.0 mcg/ml of Cloxacillin. The change in sensitivity profile is dependent on amount of INH + Cloxacillin.
  • Findings also suggests that amount of INH and Cloxacillin required is more if organism is resistant to more drugs. Findings also suggests that Cloxacillin concentration is more important than INH concentration, since 2.0 mcg/ml of Cloxacillin is effective for all strains irrespective of INH concentration.
  • Amoxycillin was also evaluated.
  • the strength of amoxycillin evaluated were 1.0 and 2.0 mcg/ml
  • MIC appears to be 1 mcg/ml.
  • MIC ranges between 1 to 2 mcg/ml.
  • Cloxacillin is a narrow spectrum penicillin with more effect on organism producing beta-lactamase and/or penicillinase, while Amoxycillin is a broad spectrum penicillin but has no activity on organisms producing beta-lactamase or penicillinase. To find out whether one or the other is more useful, same clinical isolates against which Amoxycillin was evaluated were evaluated with various concentrations of combination of Amoxycillin and Cloxacillin.
  • the combinations used has Amoxycillin and Cloxacillin in ratio of 1 :1 , 1 :2 and 1 :4 respectively.

Abstract

La multirésistance aux antituberculeux constitue aujourd'hui un problème majeur pour traiter la tuberculose. Ces souches sont résistantes au moins aux antituberculeux de première ligne comme l'INH et la rifampicine. Souvent, des souches MDR présentent une résistance à tous les agents de première ligne traditionnellement utilisés, comme l'INH, la rifampicine, la streptomycine, l'éthambutol et la pyrazinamide. L'isoniazide est l'antituberculeux le plus souvent utilisé. La résistance à l'isoniazide peut être le fait de l'expression renforcée sur inhA ou de mutations qui abaissent l'affinité enzymatique pour le NADH. Les mutations dans le gène katG qui code la catalase péroxydase sont la source de résistance la plus fréquente. Un autre mécanisme de la résistance à l'isoniazide est dû à des défauts de la NADH déshydrogénase (Ndh) de la chaîne respiratoire. Un autre mécanisme de la résistance à l'INH des mycobactéries a été récemment associé à une augmentation de l'expression du gène Ahpc. La présente invention permet de résoudre le problème de la résistance à l'INH en utilisant des pénicillines avec l'iNH. Selon la présente invention, les pénicillines, utilisées en quantité efficace, réduisent la concentration minimale inhibitrice de l'INH dans les souches multirésistantes de M. tuberculosis. La sensibilité améliorée de l'INH, se situe dans une plage qui peut être utilisée pour des applications thérapeutiques.
PCT/IB2001/001136 2000-06-28 2001-06-26 Agents permettant d'inverser la resistance aux medicaments de mycobacterium tuberculosis WO2002000165A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU66257/01A AU6625701A (en) 2000-06-28 2001-06-26 Agent for reversal of drug resistance in mycobacterium tuberculosis
APAP/P/2002/002454A AP2002002454A0 (en) 2000-06-28 2001-06-26 Agents for reversal of drug resistance in mycobacterium tuberculosis.
EA200200290A EA004875B1 (ru) 2000-06-28 2001-06-26 Применение агента для обращения устойчивости к медикаментам у mycobacterium tuberculosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN597/MUM/2000 2000-06-28
IN597MU2000 2000-06-28

Publications (2)

Publication Number Publication Date
WO2002000165A2 true WO2002000165A2 (fr) 2002-01-03
WO2002000165A3 WO2002000165A3 (fr) 2002-06-20

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AP (1) AP2002002454A0 (fr)
AU (1) AU6625701A (fr)
EA (1) EA004875B1 (fr)
WO (1) WO2002000165A2 (fr)

Cited By (14)

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EP2042517A1 (fr) 2002-09-27 2009-04-01 Xencor, Inc. Variantes FC optimisées et leurs procédés de génération
EP2053062A1 (fr) 2004-03-24 2009-04-29 Xencor, Inc. Variantes d'immunoglobine en dehors de la région Fc
US7587286B2 (en) 2003-03-31 2009-09-08 Xencor, Inc. Methods for rational pegylation of proteins
US7610156B2 (en) 2003-03-31 2009-10-27 Xencor, Inc. Methods for rational pegylation of proteins
US7642340B2 (en) 2003-03-31 2010-01-05 Xencor, Inc. PEGylated TNF-α variant proteins
US7657380B2 (en) 2003-12-04 2010-02-02 Xencor, Inc. Methods of generating variant antibodies with increased host string content
CN101810610A (zh) * 2010-04-19 2010-08-25 海南美兰史克制药有限公司 一种阿莫西林钠氟氯西林钠药物组合物脂质体注射剂
EP2325207A2 (fr) 2004-11-12 2011-05-25 Xencor, Inc. Variants de FC avec une liaison altérée à FCRN
EP2368911A1 (fr) 2003-05-02 2011-09-28 Xencor Inc. Variantes FC optimisées et leurs procédés de génération
EP2444423A1 (fr) 2007-10-31 2012-04-25 Xencor Inc. Variants de Fc dont la liaison à FcRn est altérée
EP2471813A1 (fr) 2004-07-15 2012-07-04 Xencor Inc. Variantes optimisées de Fc
EP2808343A1 (fr) 2007-12-26 2014-12-03 Xencor Inc. Variantes Fc avec liaison altérée en FcRn
US9416171B2 (en) 2011-12-23 2016-08-16 Nicholas B. Lydon Immunoglobulins and variants directed against pathogenic microbes
US9988439B2 (en) 2011-12-23 2018-06-05 Nicholas B. Lydon Immunoglobulins and variants directed against pathogenic microbes

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CN109385439A (zh) * 2018-09-18 2019-02-26 上海晶诺生物科技有限公司 一个用于构建nadh脱氢酶基因家族缺失结核分枝杆菌的重组tm4噬菌体文库及其应用

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US5686590A (en) * 1993-05-14 1997-11-11 Agresearch, New Zealand Pastoral Agriculture Research Institute Ltd. Methods and compositions for detecting and treating mycobacterial infections using an INHA gene
US5851763A (en) * 1992-09-17 1998-12-22 Institut Pasteur Rapid detection of antibiotic resistance in mycobacterium tuberculosis
US5871912A (en) * 1992-04-30 1999-02-16 Institut Pasteur Nucleic acid probes, sequences and methods for detecting mycobacterium tuberculosis resistant to isoniazid
US6200754B1 (en) * 1998-03-19 2001-03-13 Variagenics, Inc. Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes
US6329138B1 (en) * 1994-06-09 2001-12-11 Innogenetics, N.V. Method for detection of the antibiotic resistance spectrum of mycobacterium species

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US5871912A (en) * 1992-04-30 1999-02-16 Institut Pasteur Nucleic acid probes, sequences and methods for detecting mycobacterium tuberculosis resistant to isoniazid
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EP2364996A1 (fr) 2002-09-27 2011-09-14 Xencor Inc. Variantes FC optimisées et leurs procédés de génération
EP2345671A1 (fr) 2002-09-27 2011-07-20 Xencor Inc. Variantes FC optimisées et leurs procédés de génération
EP3150630A1 (fr) 2002-09-27 2017-04-05 Xencor Inc. Variantes fc optimisées et leurs procédés de génération
EP2042517A1 (fr) 2002-09-27 2009-04-01 Xencor, Inc. Variantes FC optimisées et leurs procédés de génération
EP3321282A1 (fr) 2002-09-27 2018-05-16 Xencor, Inc. Variantes fc optimisées et leurs procédés de génération
US7642340B2 (en) 2003-03-31 2010-01-05 Xencor, Inc. PEGylated TNF-α variant proteins
US7610156B2 (en) 2003-03-31 2009-10-27 Xencor, Inc. Methods for rational pegylation of proteins
US7587286B2 (en) 2003-03-31 2009-09-08 Xencor, Inc. Methods for rational pegylation of proteins
EP3838920A1 (fr) 2003-05-02 2021-06-23 Xencor, Inc. Variantes fc optimisées et leurs procédés de génération
EP2368911A1 (fr) 2003-05-02 2011-09-28 Xencor Inc. Variantes FC optimisées et leurs procédés de génération
EP3101030A1 (fr) 2003-05-02 2016-12-07 Xencor, Inc. Variants fc optimisés et methodes destinées a leur géneration
EP2221315A1 (fr) 2003-12-04 2010-08-25 Xencor, Inc. Procédés de génération de protéines variantes avec un contenu amélioré de fil hôte et compositions associées
US7930107B2 (en) 2003-12-04 2011-04-19 Xencor, Inc. Methods of generating variant proteins with increased host string content
US7657380B2 (en) 2003-12-04 2010-02-02 Xencor, Inc. Methods of generating variant antibodies with increased host string content
EP2053062A1 (fr) 2004-03-24 2009-04-29 Xencor, Inc. Variantes d'immunoglobine en dehors de la région Fc
EP2471813A1 (fr) 2004-07-15 2012-07-04 Xencor Inc. Variantes optimisées de Fc
EP3342782A1 (fr) 2004-07-15 2018-07-04 Xencor, Inc. Variantes optimisées de fc
EP2332985A2 (fr) 2004-11-12 2011-06-15 Xencor, Inc. Variants de Fc avec une liaison altérée à fcrn
EP2845865A1 (fr) 2004-11-12 2015-03-11 Xencor Inc. Variantes Fc avec liaison altérée en FcRn
EP2325207A2 (fr) 2004-11-12 2011-05-25 Xencor, Inc. Variants de FC avec une liaison altérée à FCRN
EP2325206A2 (fr) 2004-11-12 2011-05-25 Xencor, Inc. Variants de FC avec une liaison altérée à FCRN
EP2444423A1 (fr) 2007-10-31 2012-04-25 Xencor Inc. Variants de Fc dont la liaison à FcRn est altérée
EP2937361A2 (fr) 2007-10-31 2015-10-28 Xencor Inc. Fc variants ayant une liaison altérée à FcRn
EP2808343A1 (fr) 2007-12-26 2014-12-03 Xencor Inc. Variantes Fc avec liaison altérée en FcRn
EP3575317A1 (fr) 2007-12-26 2019-12-04 Xencor, Inc. Variants fc avec liaison altérée à fcrn
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Also Published As

Publication number Publication date
AP2002002454A0 (en) 2002-06-30
WO2002000165A3 (fr) 2002-06-20
AU6625701A (en) 2002-01-08
EA200200290A1 (ru) 2002-12-26
EA004875B1 (ru) 2004-08-26

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