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CN111808090B - New Deril metal-beta-lactamase-1 inhibitor - Google Patents

New Deril metal-beta-lactamase-1 inhibitor Download PDF

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CN111808090B
CN111808090B CN201910296931.3A CN201910296931A CN111808090B CN 111808090 B CN111808090 B CN 111808090B CN 201910296931 A CN201910296931 A CN 201910296931A CN 111808090 B CN111808090 B CN 111808090B
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lactamase
ndm
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bacteria
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CN111808090A (en
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刘忆霜
肖春玲
韩江雪
甘茂罗
关艳
蒙建州
王潇
李兴华
王颖
郑佳音
李东升
刘琛楠
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Abstract

The present invention relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis and/or treatment of an infection caused by bacteria, or as an inhibitor of novel deli-beta-lactamase (NDM-1), or for the manufacture of a medicament for use in antibacterial. The invention also relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with a beta-lactam antibiotic for the preparation of a medicament for the prophylaxis and/or treatment of infections caused by bacteria, a combination comprising a prophylactically or therapeutically effective amount of at least one compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a prophylactically or therapeutically effective amount of at least one beta-lactam antibiotic,
Figure DDA0002025329020000011

Description

New Deril metal-beta-lactamase-1 inhibitor
Technical Field
The invention belongs to the field of medicines, and in particular relates to a novel Deril metal-beta-lactamase-1 inhibitor which can be used for preventing and/or treating infection caused by bacteria producing the novel Deril metal-beta-lactamase-1 (NDM-1). The invention also relates to the use of the novel Deri metallo-beta-lactamase-1 inhibitor in combination with a beta-lactam antibiotic for the preparation of a medicament for the prophylaxis and/or treatment of infections caused by bacteria, and to a combination medicament comprising a prophylactically or therapeutically effective amount of at least one novel Deri metallo-beta-lactamase-1 inhibitor and a prophylactically or therapeutically effective amount of at least one beta-lactam antibiotic.
Background
Carrying a novel Deril metallo-beta-lactamase-1 (New Delhi metallo-beta-1 actanase-1, NDM-1) drug resistance gene (bla NDM ) Is a novel "superbacterium". Such bacteria carrying the NDM-1 resistance gene produce NDM-1 and are therefore also referred to as NDM-1 producing bacteria. 2008. Klebsiella pneumoniae resistant to a variety of carbapenem antibiotics (e.g., ertapenem, imipenem, and meropenem) was isolated from a 59 year old male patient in Tokuda de la in India in a urinary tract infection broth. Escherichia coli resistant to carbapenem antibiotics was isolated in nursing homes 3 months in 2008. The reason for this resistance was analyzed by phenotypic testing and subsequent isolation culture was the production of metallo-beta-lactamase (MBL), and since the active site of this metallo-beta-lactamase is two Zn ions, it was designated as New Deril metallo-beta-lactamase-1 (New Delhi metallo-beta-1 actanase-1, NDM-1).
Strains carrying the NDM-1 gene have also been found successively around the world. Currently most carry bla NDM The enterobacteriaceae are isolated from urinary tract infection, blood infection and pneumonia of patients. NDM-1 was found in Klebsiella pneumoniae at the earliest, and was found in Escherichia coli, enterobacter cloacae, acinetobacter baumannii, citrobacter, and other strains.
NDM-1-producing bacteria contain bla NDM The drug-resistant gene, NDM-1, is mediated by a plasmid, which can replicate when transformed into bacteria, and the plasmid synthesizes NDM-1 by virtue of the protein provided by the host cell. On the one hand, plasmids can be transferred between bacteria and people can be in contact transmission. On the other hand, bla is generally carried NDM The plasmids of (2) are usually integrated with various drug resistance genes such as macrolides, aminoglycosides, rifampicin, sulfamethoxazole and monocyclic beta-lactam drug resistance genes, so that bacteria can generate drug resistance to various antibiotics.
NDM-1 is a novel class of broad-spectrum metallo-beta-lactamases. The enzyme is a polypeptide consisting of 269 amino acids, has a relative molecular mass of about 27.5kD, and is a signal peptide with 28 hydrogen acids at the N-terminal, and the natural protein exists in a monomer form. As with other MBLs, NDM-1 also belongs to the alpha/beta structure, comprising a hydrophilic alpha helix and beta sheet, and the amino acid sequence homology between NDM-1 and other MBLs is very low, even though it is only 32% homologous compared to the most similar VIM-1/VIM-2 (VIM). Since NDM-1 enzyme can decompose beta-lactam ring structure, antibiotics most commonly used clinically at present, including penicillin and cephalosporin, and other atypical beta-lactam antibiotics such as cephalosporins, thiomycins, monocyclic beta-lactams and the like, all contain beta-lactam ring structure, so bacteria carrying the enzyme can resist almost all beta-lactam antibiotics.
The traditional medicine can not effectively kill the 'super bacteria' containing NDM-1, which increases the death rate of severe patients and people with low immunity infected people. Current treatment options for NDM-1 producing bacteria are very limited. For severe infections, combination therapies comprising polymyxin are preferred. However, resistance to polymyxin has emerged. Treatment of such infections is a major challenge in the medical field. The development of a novel anti-infective drug capable of effectively killing superbacteria is urgent.
Disclosure of Invention
The inventors have unexpectedly found that a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is capable of inhibiting the activity of neodeltoid metal-beta-lactamase (NDM-1). Therefore, the compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are useful as inhibitors of novel Derildimetal-beta-lactamase (NDM-1) for the prevention and/or treatment of infections caused by bacteria, in particular bacteria producing novel Derildimetal-beta-lactamase-1 (NDM-1) or bacteria resistant to beta-lactam antibiotics. The NDM-1 inhibitor can be used in combination with beta-lactam antibiotics for antibacterial, especially against NDM-1-containing superbacteria. The present invention has been completed based on the above findings.
The invention relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis and/or treatment of an infection caused by bacteria.
The invention also relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a novel Derildimetal-beta-lactamase (NDM-1) inhibitor.
The invention also relates to application of the compound shown in the formula I, stereoisomer or medicinal salt thereof in preparing medicines for resisting bacteria.
The invention also relates to the use of a pharmaceutical composition for the preparation of a medicament for the prophylaxis and/or treatment of infections caused by bacteria, wherein the pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
In certain embodiments, the pharmaceutical compositions of the present invention further comprise a β -lactam antibiotic.
The invention also relates to the use of the pharmaceutical composition in the preparation of a medicament for antibacterial purposes.
The invention also relates to the use of the pharmaceutical composition in the preparation of a medicament as a novel inhibitor of Derildimetal-beta-lactamase (NDM-1).
The invention also relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic for the preparation of a medicament for the prophylaxis and/or treatment of infections caused by bacteria.
The invention also relates to the use of a compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof in combination with a beta-lactam antibiotic for preparing a medicament for resisting bacteria.
The invention also relates to a combined medicament which comprises a prophylactically or therapeutically effective amount of at least one first active ingredient and a prophylactically or therapeutically effective amount of at least one second active ingredient, wherein the first active ingredient is a compound shown as a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, and the second active ingredient is beta-lactam antibiotics.
In certain embodiments, the combination of the invention further comprises a pharmaceutically acceptable carrier or excipient.
In certain embodiments, the first active ingredient and the second active ingredient of the combination according to the invention are in the same unit of formulation. In certain embodiments, the first active ingredient and the second active ingredient in the combination of the invention are in separate formulation units of different specifications.
In certain embodiments, the first active ingredient and the second active ingredient in the combination of the invention are administered simultaneously, separately or sequentially.
The invention also relates to a compound shown in the formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, which is used for preventing and/or treating infection caused by bacteria.
The invention also relates to a compound shown in a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, which is used for resisting bacteria.
The invention also relates to compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which are inhibitors of novel Derildimetal-beta-lactamase (NDM-1).
The present invention also relates to a method for preventing and/or treating an infection caused by bacteria comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for preventing and/or treating an infection caused by bacteria comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of at least one compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a prophylactically or therapeutically effective amount of a β -lactam antibiotic.
The present invention also relates to another method of preventing and/or treating an infection caused by bacteria comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of the combination drug of the invention.
In certain embodiments, the bacteria of the present invention are bacteria that produce novel Derileicose-beta-lactamase-1 (NDM-1) or bacteria that are resistant to beta-lactam antibiotics.
In certain embodiments, the antimicrobial of the present invention is bactericidal or inhibits bacterial activity.
In certain embodiments, the antibacterial agent of the invention is a bacterium that is resistant to novel Derileis metallo-beta-lactamase-1 (NDM-1) or a bacterium that is resistant to beta-lactam antibiotics.
In certain embodiments, the novel-beta-lactamase-1 (NDM-1) -producing bacteria of the present invention are gram-negative bacteria (e.g., klebsiella pulmonary, escherichia coli, enterobacter cloacae, acinetobacter baumannii, citrobacter, etc.) that produce novel-beta-lactamase-1 (NDM-1).
In certain embodiments, the bacteria resistant to the β -lactam antibiotic of the present invention are gram-negative bacteria resistant to the β -lactam antibiotic (e.g., klebsiella pneumoniae, escherichia coli, enterobacter cloacae, acinetobacter baumannii, citrobacter, etc.).
In certain embodiments, the β -lactam antibiotics of the present invention are selected from the group consisting of: penicillins (e.g.: penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, mexillin, temoxicillin, oxacillin, dicloxacillin, flucloxacillin, amoxicillin, pivoxilin, carbenicillin, sulbenicillin, furbenicillin, azlocillin, ticarcillin, piperacillin, etc.), cephalosporins (cefazolin, cefradine, cefalexin, cefadroxil, cefuroxime, ceftean, cefaclor, cefuroxime, cefprozil, ceftioxime, ceftriaxone, ceftazidime cefoperazone, cefixime, cefpodoxime ester, cefepime, ceftaroline ester, ceftolterone, cefalotin, ceftizoxime, cefpirome, cefamandole, cefpirane, etc.), cephalosporins (cefoxitin, cefmetazole, cefminox, etc.), carbapenems (meropenem, imipenem, panipenem, ertapenem, faropenem, biapenem, doripenem, ai Papei south, etc.), thiamycins, monocyclic beta-lactams (aztreonam, carmustine, etc.), oxacephems (Latoxef, flomoxef, etc.).
The structural formula of the compound shown in the formula I is as follows:
Figure BDA0002025326000000051
wherein:
R 1 is aryl or heterocyclyl, said aryl or heterocyclyl being optionally mono-or polysubstituted with one or more Ra, each Ra being independently selected from the group consisting of: c (C) 1-6 Alkoxy, halo C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkoxy, nitro, halogen, hydroxy, amino, C 1-6 Alkylamino, di C 1-6 Alkylamino, C 1-6 Alkanoyloxy, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R 2 is-C (=O) - (CH 2 ) n -R b Aryl or heterocyclyl, wherein R is b Selected from: hydrogen, halogen, C 1-6 Alkoxy, halo C 1-6 Alkoxy, phenoxy, phenyl, methoxyphenyl, C 1-6 Alkyl and halogenated C 1-6 Alkyl, n is 0, 1 or 2, said aryl or heterocyclyl being optionally substituted with one or more R c Single or multiple substitution, each R c Each independently selected from: c (C) 1-6 Alkoxy, halo C 1-6 Alkoxy, nitro, halogen, hydroxy, amino, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R 3 is hydrogen, halogen or C 1-6 An alkyl group;
R 4 is hydrogen, halogen or C 1-6 An alkyl group.
In certain embodiments, the heterocyclic group in the compounds of formula I of the present invention is selected from the group consisting of: thiazolyl, pyridyl, thienyl, furyl, 1, 3-benzodioxolyl.
In certain embodiments, the aryl group in the compounds of formula I of the present invention is phenyl or naphthyl.
In certain embodiments, in the compounds of formula I of the present invention, R 1 Selected from thienyl, phenyl, furyl, naphthyl, pyridyl, 1, 3-benzodioxolyl, R 1 Optionally by one or more R a Monosubstituted or polysubstituted, each R a Each independently selected from: c (C) 1-4 Alkoxy, C 3-6 Cycloalkoxy radicals C 1-4 Alkylthio, nitro, halogen, hydroxy, amino, C 1-4 Alkylamino, di C 1-4 Alkylamino, C 1-4 Alkanoyloxy, C 1-4 An alkyl group.
In certain embodiments, in the compounds of formula I of the present invention, R 1 Optionally mono-or polysubstituted by one or more Ra, each Ra being independently selected from: fluorine, chlorine, bromine, iodine, methoxy, ethoxy, methyl, dimethylamino, ethyl, t-butyl, nitro, isopropyl, methylthio, acetoxy, formyloxy, propionyloxy, diethylamino, halomethyl, haloethyl, halopropyl, propoxy, hydroxy, nitro, amino, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopentyloxy, cyclohexyloxy, cyclopropyloxy, cyclobutyloxy.
In certain embodiments, in the compounds of formula I of the present invention, R 1 Selected from:
Figure BDA0002025326000000061
Figure BDA0002025326000000071
in certain embodiments, in the compounds of formula I of the present invention, R 2 Selected from thiazolyl, pyridinyl, phenyl, said thiazolyl, pyridinyl or phenyl optionally substituted with one or more R c Monosubstituted or polysubstituted, each R c Each independently selected from: methoxy, ethoxy, propoxy, nitro, fluoro, chloro, bromo, iodo, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
In certain embodiments, in the compounds of formula I of the present invention, R 2 is-C (=O) - (CH 2 ) n -R b Wherein R is b Selected from: hydrogen gasFluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, butoxy, phenoxy, phenyl, methoxyphenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, n being 0, 1 or 2.
In certain embodiments, in the compounds of formula I of the present invention, R 2 Selected from: -C (=o) -CH 3 、-C(＝O)-CH 2 -CH 3 、-C(＝O)-(CH 2 ) 2 -CH 3 、-C(＝O)-CH(CH 3 ) 2 、 -C(＝O)-CH 2 -CH(CH 3 ) 2 、
Figure BDA0002025326000000081
In certain embodiments, in the compounds of formula I of the present invention, R 3 Is hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.
In certain embodiments, in the compounds of formula I of the present invention, R 3 Is n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.
In certain embodiments, in the compounds of formula I of the present invention, R 3 Is methyl, ethyl, n-propyl or isopropyl.
In certain embodiments, in the compounds of formula I of the present invention, R 3 Hydrogen, fluorine, chlorine, bromine or iodine.
In certain embodiments, in the compounds of formula I described herein, R3 is hydrogen or chloro.
In certain embodiments, in the compounds of formula I described herein, R3 is hydrogen.
In certain embodiments, in the compounds of formula I described herein, R3 is chloro.
In certain embodiments, in the compounds of formula I of the present invention, R 4 Is hydrogen, fluorine, chlorine, bromine,Iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.
In certain embodiments, in the compounds of formula I of the present invention, R 4 Is n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.
In certain embodiments, in the compounds of formula I of the present invention, R 4 Is fluorine, chlorine, bromine or iodine.
In certain embodiments, in the compounds of formula I described herein, R4 is hydrogen, methyl, ethyl, n-propyl, or isopropyl.
In certain embodiments, in the compounds of formula I of the present invention, R 4 Is hydrogen or methyl.
In certain embodiments, in the compounds of formula I of the present invention, R 4 Is hydrogen.
In certain embodiments, in the compounds of formula I of the present invention, R 4 Is methyl.
In certain embodiments, the compounds of formula I described herein are selected from the compounds shown in Table 1, including compounds IMB-XH1, IMB-XH1Q, and IMB-XH1-1 through IMB-XH1-110.
Various terms and phrases used herein have a common meaning known to those skilled in the art, and unless otherwise indicated, the terms and phrases used herein have a meaning inconsistent with the known meaning and meaning consistent with the context of the present invention.
The term "beta-lactam antibiotics (beta-lactams)" as used herein refers to a broad class of antibiotics having a beta-lactam ring in the chemical structure, including the most commonly used penicillins and cephalosporins in clinical use, as well as the newly developed cephalosporins, carbapenems, thiamycins, monocyclobeta-lactams, oxacephems and other atypical beta-lactam antibiotics. Specific beta-lactam antibiotics include, but are not limited to:
Penicillins such as: penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, mexillin, temoxicillin, oxacillin, dicloxacillin, flucloxacillin, amoxicillin, pivoxillin, carbenicillin, sulbenicillin, furbenicillin, azlocillin, ticarcillin, piperacillin and the like,
cephalosporins such as: cefazolin, cefradine, cefprozil, cefuroxime, cefotiam, cefaclor, cefuroxime, cefprozil, ceftioxime, ceftriaxone, ceftazidime, cefoperazone, cefixime, cefpodoxime proxetil, ceftaroline fosamil, ceftolterone, cefalotin, ceftizoxime, cefpirome, cefamandole, cefpirate, etc.,
cephalosporins such as: cefoxitin, cefmetazole, cefminox, etc.,
monocyclic beta-lactams such as: aztreonam, carborundum and the like,
carbapenems such as: meropenem, imipenem, panipenem, ertapenem, faropenem, biapenem, doripenem, ai Papei south and the like,
oxacephems such as: and Laroxb, flomoxef, etc.
The term "aryl" as used herein refers to a mono-or bi-cyclic aromatic system comprising at least one unsaturated aromatic ring, preferably an aryl group having 6 to 10, i.e. 6,7,8,9 or 10 carbon atoms. Specific examples include, but are not limited to, phenyl, naphthyl, and the like.
The term "heterocyclyl" as used herein refers to a monocyclic or bicyclic saturated, partially saturated or unsaturated aromatic or aliphatic cyclic system optionally substituted with at least one and up to four heteroatoms independently selected from N, O or S, preferably a mono-heterocyclyl having 4 to 7 atoms (containing 4, 5, 6 or 7 atoms) or a di-heterocyclyl having 7 to 11 atoms (containing 7,8,9, 10 or 11 atoms), for example a 5-6 membered mono-heteroaryl, a 7-11 membered di-heteroaryl, an azacyclic or a 4-6 membered aliphatic azacyclic. Specific examples include, but are not limited to, imidazolyl, thiazolyl, pyridyl, thienyl, furyl, 1, 3-benzodioxolyl.
The term "C" as used in the present invention 1-6 Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. C 1-4 An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl.
The term "C" as used in the present invention 1-6 Alkoxy "means C as defined above 1-6 Groups obtained by linking carbon atoms to oxygen atoms on alkyl groups, e.g. "C 1-4 Specific examples of alkoxy "include, but are not limited to methoxy, ethoxy, or propoxy, and the like.
The term "C" as used in the present invention 1-6 Alkylthio "means C as defined above 1-6 Groups obtained by linking carbon atoms of alkyl groups to sulfur atoms, e.g. "C 1-4 Alkylthio ", specific examples include, but are not limited to, methylthio, ethylthio, propylthio, and the like.
The term "C" as used in the present invention 3-6 Cycloalkoxy "refers to a group having 3 to 6 carbon atoms, such as a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, bonded to an oxygen atom, and specific examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
The term "C" as used in the present invention 1-6 Alkanoyl "means C as defined above 1-6 Specific examples of the group obtained by linking an alkyl group to one end of a carbon atom in a carbonyl group include, but are not limited to, formyl, acetyl, propionyl and the like.
The term "C" as used in the present invention 1-6 Alkanoyloxy "means C as defined above 1-6 And (3) a group obtained by connecting an alkanoyl group to an oxygen atom. Specific examples include, but are not limited to, formyloxy, acetoxy, propionyloxy, and the like.
The term "halogenated C" as used in the present invention 1-6 Alkyl "means C as defined above 1-6 A group obtained by substituting one or more hydrogen atoms on an alkyl group with halogen. Specific examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethylA group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a fluoroethyl group, a fluoropropyl group, a fluoroisopropyl group, a fluoron-butyl group, a fluoroisobutyl group, a fluorosec-butyl group, a fluorotert-butyl group, a fluoron-pentyl group, a fluoron-hexyl group, and the like.
The term "halogen" as used in the present invention refers to fluorine, chlorine, bromine, iodine.
The term "amino" as used in the present invention means NH 2 -。
The term "C" as used in the present invention 1-6 Alkylamino "means C as defined above 1-6 Specific examples of alkyl-substituted amino groups include, but are not limited to, methylamino, ethylamino, propylamino, and the like.
The term "bic" as used in the present invention 1-6 Alkylamino "means C as defined by two of the foregoing 1-6 Specific examples of alkyl substituted amino groups include, but are not limited to, dimethylamino, diethylamino, dipropylamino, and the like.
The term "subject" as used herein includes mammals and humans, preferably humans.
The term "pharmaceutically acceptable salt" as used herein means a salt of a compound of the invention which is pharmaceutically acceptable and which has the desired pharmacological activity of the parent compound. Such salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic acids; such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when acidic protons present on the parent compound are replaced with metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.
The pharmaceutical composition of the invention contains a compound shown in a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Such vectors include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin. The excipient refers to an addition to the main drug in the pharmaceutical formulation. The traditional Chinese medicine composition has stable property, no incompatibility with the main medicine, no side effect, no influence on curative effect, no deformation, dry crack, mildew and moth damage at normal temperature, no harm to human body, no physiological effect, no chemical or physical effect with the main medicine, no influence on the content measurement of the main medicine, and the like. Such as binders, fillers, disintegrants, lubricants in the tablet; wine, vinegar, medicinal juice and the like in the traditional Chinese medicine pill; a base portion in a semisolid formulation ointment, cream; preservatives, antioxidants, flavoring agents, fragrances, co-solvents, emulsifiers, solubilizers, tonicity adjusting agents, colorants and the like in liquid formulations can be referred to as excipients and the like.
The pharmaceutical compositions of the compounds of the present invention may be administered in any of the following ways: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an explanted reservoir. Among them, oral, intraperitoneal or intravenous administration is preferable.
The term "effective amount" as used herein refers to an amount sufficient to achieve, or at least partially achieve, the desired effect. For example, a prophylactically effective amount refers to an amount sufficient to prevent, arrest, or delay the onset of a disease; a therapeutically effective amount refers to an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determination of such effective amounts is well within the ability of those skilled in the art. For example, the amount effective for therapeutic use will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously, and the like.
The amount of a compound of the invention administered to a subject depends on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, weight and tolerance to the drug, and also on the type of formulation and mode of administration of the drug, and on factors such as the period or time interval of administration. One skilled in the art will be able to determine the appropriate dosage based on these factors and other factors. In general, the compounds of the invention may be used in therapeutic daily doses of about 1 to 800 mg, which daily doses may be administered as appropriate in one or more divided doses. The compounds of the invention may be provided in dosage units which may be present in amounts of from 0.1 to 200 mg, for example from 1 to 100 mg.
The term "combination drug" in the present invention refers to a drug which combines a compound shown in formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof with a beta-lactam antibiotic, and the combination drug can be a pharmaceutical composition composed of two active ingredients of the compound shown in formula I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof with the beta-lactam antibiotic, or can be two pharmaceutical compositions respectively prepared from the compound shown in formula I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof with the beta-lactam antibiotic. In the combination, the compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the β -lactam antibiotic may be administered simultaneously or separately to a subject in need thereof; or firstly applying the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof, and then applying the beta-lactam antibiotics after a certain time interval; or the beta-lactam antibiotic is firstly applied, and then the compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof is applied after a certain time interval.
The beneficial technical effects of the invention
The compound shown in the formula I, the stereoisomer or the pharmaceutically acceptable salt thereof can inhibit the activity of the novel Deril metal-beta-lactamase (NDM-1), can be used as a novel Deril metal-beta-lactamase (NDM-1) inhibitor for preventing and/or treating the infection caused by bacteria, in particular the infection caused by bacteria producing the novel Deril metal-beta-lactamase-1 (NDM-1) or bacteria resistant to beta-lactam antibiotics. The NDM-1 inhibitor can be used in combination with beta-lactam antibiotics for antibacterial, especially against NDM-1-containing superbacteria.
Drawings
FIG. 1 is a graph showing the relationship between the reaction rate of the compound IMB-XH1 and the concentration of the NDM-1 enzyme at various concentrations;
FIG. 2 is a graph showing the reaction rate of the compound IMB-XH1Q at various concentrations in relation to the concentration of the NDM-1 enzyme;
FIG. 3 is a Lineweaver-Burke curve for the compound IMB-XH1 at various concentrations;
FIG. 4 is a Lineweaver-Burke plot of the compound IMB-XH1Q at various concentrations;
FIG. 5; fluorescence emission spectrum change curves of NDM-1 enzyme under the action of compounds IMB-XH1 with different concentrations;
FIG. 6; the compound IMB-XH1 at different temperatures causes a Stern-Volmer curve for fluorescence quenching of the NDM-1 enzyme.
Detailed Description
Embodiments of the present invention will be described in detail with reference to the following examples, which are only for illustration of the present invention and should not be construed as limiting the scope of the present invention, as will be understood by those skilled in the art. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The experimental materials, reagents, instruments involved in the following examples are as follows:
NDM-1 enzyme can be prepared, for example, by the methods disclosed in Shi X.et al (Shi X.; wang M.; huang S.; han J.; chu W.; xiao C.; zhang E.; qin s.H2 des: an acyclic adjuvant potentiates meropenem activity in vitro against metallo-beta-lactate-producing enterobacterales [ J ]. Eur.J. Med. Chem.2019, 167:367-376).
The empty plasmid control bacterium E.coli BL21 (DE 3) (pET-30 a (+)) is obtained by transforming plasmid pET-30a (+) into expression host bacterium E.coli BL21 (DE 3), and the transformation method is a heat shock method. Wherein the expression host strain E.coli BL21 (DE 3) was purchased from the whole gold organism Co.
For example, the method of transforming plasmid pET-30a (+) into E.coli BL21 (DE 3) competent cells includes:
1) Adding 100 mu L of competent cells melted on an ice bath into a centrifuge tube, adding 10 mu L of plasmid pET-30a (+) into the centrifuge tube, gently mixing the mixture, and placing the mixture in the ice bath for 30min;
2) Heat shock is carried out in a water bath at 42 ℃ for 60s, and the centrifuge tube is quickly transferred into an ice bath to be cooled for 3 min after heat shock; (this procedure does not require shaking the centrifuge tube)
3) Adding 900 mu L of sterile LB liquid medium without antibiotics into a centrifuge tube, uniformly mixing, placing at 37 ℃, culturing for 1h at 45r.p.m. to revive bacteria, and expressing a resistance gene coded by a plasmid;
4) Shaking the obtained bacterial liquid uniformly, respectively sucking 100 mu L and 200 mu L, coating on an LB agar solid plate (containing 50 mu g/ml Kan), and uniformly coating cells;
5) Centrifuging the residual bacterial liquid at room temperature of 4,000r.p.m. for 2min, reserving 200 mu L of supernatant, re-suspending the bacterial sediment, sucking 100 mu L, and repeating the operation of the step 4;
6) The plate was placed in a 37℃incubator until the liquid was absorbed, the plate was inverted, and incubated overnight at 37 ℃.
Recombinant NDM-1 expression engineering bacteria E.coli BL21 (DE 3) (pET-30 a (+) -NDM-1) are provided by Xuefu teacher laboratory of medical biotechnology institute of China academy of medical science.
E.coli ATCC25922, E.coli13-1 (clinical isolate), K.pneumoniae ATCC700603 (clinical isolate), K.pneumoniae 1705 (clinical isolate), K. pneumoniae ATCC BAA2146 from Xuefu teacher laboratory, institute of medical biotechnology, national academy of sciences of medicine.
Ampicillin, ticarcillin, piperacillin, penicillin, cefalotin, cefoperazone and aztreonam standards were all purchased from the national food and drug testing institute.
The compounds IMB-XH1, IMB-XH1Q and IMB-XH1-1 to IMB-XH1-110 are all available from the Williams technology Co.
DMSO (CAS#: 200-664-3) is available from Amresco.
HEPES (CAS#: 7365-45-9) was purchased from Amresco.
EDTA (CAS#: 60-00-4) was purchased from BBI life sciences.
MEPM (meropenem, CAS#: 119478-56-7) was purchased from TCI.
10mM HEPES solution, its preparation method is: 2.38g HEPES was weighed, dissolved in 1000ml distilled water, pH was adjusted to 7.5,0.45 μm with 10M NaOH, filtered and stored at 4 ℃.
MH broth culture medium, its preparation method is: 25g of MHB dry powder, adding water to a final volume of 1000mL, mixing and sterilizing at 121 ℃ for 15min.
The microplate reader Enspire 2300, multiabel Reader, available from Perkinelmer Inc.
Inverted microscope CKX41, available from OLYMPUS corporation.
The concentration unit "M" used in the following experiments represents mol/L, mM represents mmol/L, and μM represents μmol/L.
Experimental example 1 in vitro enzyme Activity inhibition assay for NDM-1 inhibitor
In the experiment, the NDM-1 inhibitor is compound IMB-XH1, compound IMB-XH1Q and compound IMB-XH 1-IMB-XH 1-110 shown in Table 1, and the NDM-1 inhibitor is prepared into mother liquor with the concentration of 10mg/mL by using DMSO, and the mother liquor is dissolved and diluted by using DMSO according to the requirement in the experiment process. The substrate used in this experiment was meropenem (MEPM), which was first prepared with distilled water to a concentration of 10mM, and stored at-20deg.C, and the mother liquor was diluted with 10mM HEPES buffer as needed during the experiment. The NDM-1 enzyme used in this experiment was first prepared with 10mM HEPES buffer to a concentration of 2.8U (3.78 nM), and the mother liquor was diluted with 10mM HEPES buffer as needed during the experiment.
The inhibitory activity of an NDM-1 inhibitor on NDM-1 was tested in 96-well UV plates. The experimental method comprises the following steps:
(1) In 200. Mu.l of the enzyme reaction system, the final concentrations of the NDM-1 inhibitor were set to 20. Mu.g/mL, 10. Mu.g/mL, 5. Mu.g/mL, 2.5. Mu.g/mL, 1.25. Mu.g/mL, 0.625. Mu.g/mL, 0.3125. Mu.g/mLl and 0. Mu.g/mL, respectively. Diluting each NDM-1 inhibitor mother solution with DMSO according to the corresponding final concentration, then adding 2 mu L of each mother solution into a 96-well UV plate, adding 2 mu L of blank solvent DMSO into a control group, and carrying out three parallel groups;
(2) Diluting the NDM-1 enzyme mother liquor with 10mM HEPES buffer solution, adding 98 mu L of diluted enzyme solution into each well to make the final concentration of the enzyme solution in the enzyme system be 3.78nM, and incubating at 37 ℃ for 15 min;
(3) The final MEPM concentration was set at 100. Mu.M, the substrate MEPM solution was diluted with 10mM HEPES buffer, and then 100. Mu.L of the diluted substrate solution was added to each well, respectively, to initiate the reaction;
(4) Subsequently, 96-well UV plates were placed in an ELISA apparatus to determine the OD of the system every 1min 300 Absorbance at 300nm, continuously at 37deg.C for 60min, calculating enzyme inhibition rate at each concentration of inhibitor, and analyzing IC of each inhibitor by GraphPad Prism5 software 50 . Wherein the calculation formula of the enzyme inhibition rate is as follows:
Figure BDA0002025326000000171
wherein:
Figure BDA0002025326000000172
t1 and T2 are the detection times, respectively.
At a concentration of 20. Mu.g/mL, the inhibition rate of each inhibitor to NDM-1 enzyme is shown in Table 1, and IC of each inhibitor to NDM-1 enzyme 50 See table 2.
TABLE 1 inhibition of NDM-1 enzyme by NDM-1 inhibitor at 20 μg/mL
Figure BDA0002025326000000173
Figure BDA0002025326000000181
Figure BDA0002025326000000191
Figure BDA0002025326000000201
Figure BDA0002025326000000211
Figure BDA0002025326000000221
Figure BDA0002025326000000231
Figure BDA0002025326000000241
Figure BDA0002025326000000251
Figure BDA0002025326000000261
Figure BDA0002025326000000271
Figure BDA0002025326000000281
Figure BDA0002025326000000291
Figure BDA0002025326000000301
Figure BDA0002025326000000311
Figure BDA0002025326000000321
Figure BDA0002025326000000331
Figure BDA0002025326000000341
Figure BDA0002025326000000351
Figure BDA0002025326000000361
Figure BDA0002025326000000371
Figure BDA0002025326000000381
Figure BDA0002025326000000391
TABLE 2 half inhibition concentration IC of NDM-1 inhibitor on NDM-1 enzyme 50
Figure BDA0002025326000000392
Experimental example 2 kinetic study of NDM-1 inhibitor on NDM-1
In the experiment, the NDM-1 inhibitor is a compound IMB-XH1 and a compound IMB-XH1Q, the NDM-1 inhibitor is firstly prepared into a mother solution with the concentration of 10mg/mL by using DMSO, and the mother solution is dissolved and diluted by using DMSO according to the requirement in the experiment process. The substrate used in this experiment was meropenem (MEPM) which was first prepared with water to a stock solution at a concentration of 10mM, and the stock solution was diluted with 10mM HEPES buffer as needed during the experiment. The NDM-1 enzyme used in this experiment was first prepared with 10mM HEPES buffer to a concentration of 2.8U (3.78 nM), and the mother liquor was diluted with 10mM HEPES buffer as needed during the experiment.
2.1 identification of reversible and irreversible inhibition
The experimental method comprises the following steps:
(1) In 200. Mu.l of the enzyme reaction system, the final concentration of each NDM-1 inhibitor was set to five concentration gradients of 0, 2.5, 5.0, 10.0 and 20.0. Mu.g/mL, respectively. Diluting each NDM-1 inhibitor mother liquor with DMSO according to the corresponding final concentration, then adding 2 mu L of each mother liquor into a 96-well UV plate, adding 2 mu L of blank solvent DMSO into a control group, and carrying out three parallel groups;
(2) For different concentrations of NDM-1 inhibitor, 8 NDM-1 enzyme concentration gradients were set, with final enzyme concentrations in the system of 38.10, 19.05, 12.67, 9.53, 7.62, 6.35, 4.76 and 3.81nmol/L, respectively. Diluting the NDM-1 enzyme mother solution with 10mM HEPES buffer solution according to the corresponding final concentration, adding 98 mu L of diluted enzyme solution into each well of a 96-well UV plate, and incubating at 37 ℃ for 15min;
(3) The final concentration of substrate MEPM was set at 100. Mu.M, substrate MEPM stock solution was diluted with 10mM HEPES buffer, and then 100. Mu.L of diluted substrate solution was added to each well, respectively, to initiate the reaction;
(4) Placing the 96-hole UV plate in an enzyme-labeled instrument at 37 ℃, detecting the light absorption value once every 1min, detecting the wavelength of 300nm, and continuously measuring for 60min;
(5) And respectively calculating the reaction rate of each NDM-1 inhibitor concentration, drawing a concentration relation curve of the reaction rate and the enzyme at different NDM-1 inhibitor concentrations, and identifying whether the inhibitor can reversibly inhibit the NDM-1 enzyme. The experimental results are shown in fig. 1 and 2. The calculation formula of the reaction rate is shown below.
Figure BDA0002025326000000401
Wherein T1 and T2 are the detection times, respectively.
When no inhibitor is added in the enzyme activity measuring system, a straight line passing through the origin can be obtained; when a certain amount of irreversible inhibitor is added into the enzyme activity measuring system, the inhibitor can deactivate a certain amount of enzyme, so that the enzyme activity is only shown when the added enzyme amount is larger than the amount of the irreversible inhibitor, and the action of the irreversible inhibitor is equivalent to moving the origin to the right, and the slope is unchanged; when the enzyme activity measuring system is added with a certain amount of reversible inhibitor, a straight line passing through the origin but decreasing in slope is obtained because the amount of inhibitor is constant. As can be seen from FIGS. 1 and 2, as the inhibitor concentration increases, a straight line passing through the origin but gradually decreasing in slope is obtained, and thus both the compound IMB-XH1 and the compound IMB-XH1Q are reversible inhibitors of the NDM-1 enzyme.
2.2 determination of type of inhibition
The experimental method comprises the following steps:
1) In 200. Mu.l of the enzyme reaction system, the final concentration of the NDM-1 inhibitor was set to five concentration gradients of 0, 0.25, 0.5, 1 and 10. Mu.g/ml; diluting each NDM-1 inhibitor mother solution with DMSO according to the corresponding final concentration, adding 2 mu L of each mother solution into a 96-well UV plate, and adding 2 mu L of blank solvent DMSO into a control group, wherein each group is three in parallel;
2) The final concentration of NDM-1 enzyme was set at 9.53nM, about 3.5U; diluting the NDM-1 enzyme mother solution with 10mM HEPES buffer solution according to the corresponding final concentration, adding 98 mu L of diluted enzyme solution into each well of a 96-well UV plate, and incubating at 37 ℃ for 15min;
3) Setting eight gradients of substrate MEPM final concentrations of 0, 6.25, 12.5, 25, 50, 100, 200 and 400 μmol/L for different concentrations of NDM-1 inhibitor; diluting the substrate MEPM stock solution with 10mM HEPES buffer solution according to the corresponding final concentration, and then adding 100 mu L of diluted substrate solution into each well respectively to start the reaction;
4) Placing the 96-hole UV plate in an enzyme-labeled instrument at 37 ℃, detecting the light absorption value once every 1min, detecting the wavelength to be 300nm, and continuously measuring for 60min;
5) Respectively calculating the reaction rate of each NDM-1 inhibitor under different concentrations, drawing a Lineweaver-Burke curve under different NDM-1 inhibitor concentrations, namely a double reciprocal curve of the reaction rate to the substrate concentration, and calculating K i Values, the type of inhibition of NDM-1 by each NDM-1 inhibitor was analyzed. The experimental results are shown in fig. 3 and 4.
And (3) respectively making a Lineweaver-Burke curve under different inhibitor concentrations by using a Lineweaver-Burk plotting method and using the inverse substrate concentration of 1/S as an abscissa and the inverse reaction rate of 1/V as an ordinate. As shown in fig. 3 and 4, 1/V and 1/S are in a linear relationship, the type of inhibitor can be determined from the intersection point position of straight lines, when the concentration of the inhibitor is increased, the slope of the straight lines is increased, and if all the straight lines intersect with the positive half axis of the vertical axis, the inhibitor is competitive; if all straight lines intersect with the horizontal axis negative half axis, the inhibitor is a non-competitive inhibitor; if all lines are in a set of parallel lines, then they are anti-competitive inhibitors.
As can be seen from FIGS. 3 and 4, at different inhibitor concentrations, the compounds IMB-XH1 and IMB-XH1Q inhibit the activity of NDM-1 in a non-competitive inhibition manner, and the inhibition constant K of the compound IMB-XH1 is calculated i Inhibition constant K of the Compound IMB-XH1Q at 3.636. Mu. Mol/L i Is 0.50 mu mol/L.
Experimental example 3 evaluation of in vitro antibacterial Activity of different NDM-1 inhibitors against NDM-1-producing bacteria
To examine whether different NDM-1 inhibitors have an antibacterial effect on NDM-1-producing bacteria, a bacterial-level drug sensitivity test was performed using recombinant NDM-1 expression engineering bacteria and other NDM-1-producing bacteria clinically isolated, respectively, and the Minimum Inhibitory Concentration (MIC) was determined by a broth microdilution method.
In the experiment, the NDM-1 inhibitor is a compound IMB-XH1 and a compound IMB-XH1Q, the NDM-1 inhibitor is firstly prepared into a mother solution with the concentration of 10mg/mL by using DMSO, and the mother solution is dissolved and diluted by using DMSO according to the requirement in the experiment process.
The substrates used in this experiment were β -lactam antibiotics (including ampicillin, ticarcillin, piperacillin, penicillin, cefalotin, cefoperazone, meropenem and aztreonam), wherein ampicillin, penicillin, meropenem were formulated with water to a mother liquor at a concentration of 25.6mg/L, and ticarcillin, piperacillin, cefalotin, cefoperazone, aztreonam were formulated with DMSO to a mother liquor at a concentration of 25.6 mg/L.
The experimental method comprises the following steps:
(1) According to the design requirements of drug sensitivity test, 100 mu L of beta-lactam antibiotics (ampicillin, ticarcillin, piperacillin, penicillin, ceftiofur, cefoperazone, meropenem and aztreonam) with concentration gradients of 256.0, 128.0, 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5 and 0.25 mu g/mL are respectively added into a sterile 96-well plate, and the gradients are respectively 5 multiplied by 10 5 Diluting beta-lactam antibiotic mother liquor by using a Mueller-Hinton (MH) broth culture medium of CFU/mL NDM-1-producing bacteria;
(2) The NDM-1 inhibitor was set to two concentration gradients of 10. Mu.g/mL and 20. Mu.g/mL, and 2. Mu.L of NDM-1 inhibitor solution was added to each well. A solvent control well was also provided, and 2. Mu.L of DMSO was added to the solvent control well.
8 positive growth control wells (100. Mu.L of bacteria-free MH broth medium) and 8 negative growth control wells (100. Mu.L of bacteria-free MH broth medium) were additionally placed in the culture plate;
(3) Sealing the periphery of the 96-well plate with a sealing film after the 96-well plate is covered, and placing the sealed plate in a incubator for incubation at 37 ℃;
(4) After 24 hours, observing a positive growth control hole and a negative growth control hole, observing the bacterial growth condition of each test hole when the positive growth control hole and the negative growth control hole are obviously different, judging whether the inhibitor and the beta-lactam antibiotics have combined antibacterial effect or not, and recording the result; after 48 hours, the result of confirmation recording was observed again.
The antibacterial effect of the compounds IMB-XH1 and IMB-XH1Q in combination with various beta-lactam antibiotics, such as ampicillin, ticarcillin, piperacillin, penicillin, cefalotin, cefoperazone, meropenem and aztreonam, on recombinant NDM-1 expressing engineering bacteria is shown in tables 3 and 4. The results show that the compound IMB-XH1 and the compound IMB-XH1Q have an inhibitory effect on recombinant NDM-1 expression engineering bacteria when being used in combination with beta-lactam antibiotics.
TABLE 3 antibacterial effect of Compound IMB-XH1 on recombinant NDM-1 expression engineering bacteria and empty plasmid control bacteria
Figure BDA0002025326000000431
TABLE 4 antibacterial action of Compound IMB-XH1Q against recombinant NDM-1 expression engineering bacteria and empty plasmid control bacteria
Figure BDA0002025326000000432
The antibacterial effect of the combination of compounds IMB-XH1 and IMB-XH1Q on other NDM-1 producing bacteria (MEPM) is shown in Table 5.
TABLE 5 MIC of the compounds IMB-XH1 and IMB-XH1Q in combination with MEPM for other NDM-1 producing bacteria (. Mu.g/ml)
Figure BDA0002025326000000441
Experimental example 4 investigation of interaction of NDM-1 inhibitor with NDM-1 enzyme and its mode of action by fluorescence quenching
In the experiment, the NDM-1 inhibitor is a compound IMB-XH1, the compound IMB-XH1 is firstly prepared into a mother solution with the concentration of 10mg/mL by using DMSO, and the mother solution is dissolved and diluted by using DMSO according to the requirement in the experiment process.
The NDM-1 enzyme used in this experiment was first prepared with 10mM HEPES buffer to a concentration of 2.8U (3.78 nM), and the mother liquor was diluted with 10mM HEPES buffer as needed during the experiment.
4.1 fluorescence quenching method for determining interaction of Compound IMB-XH1 with NDM-1 enzyme
1) The final volume of the samples is 200 μl, the temperature is set to 37 ℃, all fluorescence measurements are carried out in a black opaque 96-well plate, and the detection is carried out by an enzyme-labeling instrument by adopting a top reading method;
2) Diluting the compound IMB-XH1 mother liquor with DMSO at the corresponding final concentration, and then adding 100. Mu.L of diluted compound IMB-XH1 solution to each well, wherein the final concentration of the compound IMB-XH1 is set to seven gradients of 0.015625, 0.03125, 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/mL;
3) Diluting the NDM-1 enzyme mother liquor with 10mM HEPES buffer solution according to the corresponding final concentration, adding 100 mu L of diluted NDM-1 enzyme solution into each well, and setting the final concentration of the NDM-1 enzyme solution to be 100 mu g/ml;
4) Setting an NDM-1 inhibitor control group and an NDM-1 enzyme control group simultaneously, wherein the NDM-1 inhibitor control group is added with 200 mu L of compound IMB-XH1 with the concentration of 2mg/mL, and the NDM-1 enzyme control group is added with 200 mu L of NDM-1 enzyme solution with the concentration of 100 mu g/mL;
5) Setting the excitation wavelength as 280nm, scanning the emitted light of 300-500 nm, drawing the fluorescence emission spectrum change curve of the NDM-1 enzyme under the action of the NDM-1 inhibitor with different concentrations, and analyzing the fluorescence quenching condition.
4.2 study of the mode of action of fluorescence quenching
1) According to the method in 4.1, the fluorescence quenching conditions of the interaction of the compound IMB-XH1 and the NDM-1 enzyme at different temperatures are detected, wherein the temperatures are set to 27 ℃, 37 ℃ and 47 ℃;
2) Selecting a wavelength at which the NDM-1 enzyme emits a maximum fluorescence value in the absence of the NDM-1 inhibitor, and calculating a fluorescence value (F 0 ) Ratio F of fluorescence value (F) emitted by different concentration inhibitors 0 F, NDM-1 inhibitorConcentration [ Q ]]In abscissa, F 0 Drawing a Stern-Volmer curve of NDM-1 enzyme fluorescence quenching at different temperatures by using the vertical coordinate of/F to obtain a Stern-Volmer equation;
3) The quenching constants between the compounds IMB-XH1 and NDM-1 were deduced according to the equation, and the analysis gave a possible mode of action of the compounds IMB-XH1 to cause fluorescence quenching of the NDM-1 enzyme.
The interaction mechanism of the NDM-1 inhibitor (the compound IMB-XH 1) and the NDM-1 enzyme is initially explored by using a fluorescence quenching method. Fluorescence of the NDM-1 enzyme is mainly generated by tryptophan molecules, and the sequence of the NDM-1 enzyme contains 4 tryptophan, so that when a compound binds to the NDM-1 enzyme, the microenvironment around the tryptophan changes, and the fluorescence intensity is reduced. The change of fluorescence emission spectrum of NDM-1 enzyme under the action of NMD-1 inhibitor with different concentrations is shown in FIG. 5. Under the condition of 37 ℃, under the condition of 280nm fixed excitation light, the NDM-1 enzyme has the strongest fluorescence emission at 338nm, and the inhibitor compound IMB-XH1 under the same condition does not interfere with the intrinsic fluorescence. As the concentration of the compound IMB-XH1 increases, the maximum fluorescence of the NDM-1 enzyme gradually decreases and a "red shift" phenomenon, which shifts to a larger wavelength, is generated, indicating that an interaction between the compound IMB-XH1 and the NDM-1 enzyme occurs, resulting in a change in the tertiary structure of the protein and the microenvironment near tryptophan. The results indicate that the compound IMB-XH1 may form hydrogen bonds with amino or hydroxyl groups of the NDM-1 enzyme, resulting in a polar environment in the vicinity of tryptophan.
The fluorescence quenching action mode is divided into static quenching and dynamic quenching, and can be judged by the change of the degree of the protein fluorescence quenching caused by the compound at different temperatures. The quenching of fluorescence caused by the increased collision movement between molecules and the accelerated diffusion rate is intensified as the temperature increases, and the quenching constant at this time increases as the temperature increases, and the opposite case is static quenching.
In this experimental example, three temperatures of 27℃and 37℃and 47℃were selected to detect the fluorescence quenching of the NDM-1 enzyme by the compound IMB-XH1, and the Stern-V at different temperatures was plotted o lmer curve, as shown in fig. 6. As can be seen from FIG. 6, the quenching constant of the compound IMB-XH1 increases with increasing temperatureLarge, similar to dynamic quenching.
From the Stern-Volmer curve, the Stern-Volmer equation is derived: f (F) 0 /F＝1+K q τ 0 [Q]＝ 1+K sv [Q]Thereby calculating the quenching constant K q . The Stern-Volmer equation for the interaction of the compounds IMB-XH1 and NDM-1 enzymes at different temperatures and the quenching constants are shown in Table 6.
TABLE 6 Stern-Volmer equation for interaction of Compounds IMB-XH1 and NDM-1 enzymes at different temperatures and quenching constants
T(℃) Stern-Volmer equation K q (L/mol·s) R2
27 y＝23.30×10 3 [Q]+1 2.3×10 12 0.98
37 y＝23.35×10 3 [Q]+1 2.3×10 12 0.99
47 y＝30.87×10 3 [Q]+1 3.1×10 12 0.91

Claims (21)

1. Use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and/or treatment of an infection caused by bacteria, wherein:
The bacteria are bacteria producing novel Derilmetal-beta-lactamase-1,
the compound is selected from:
Figure FDA0004136029870000011
Figure FDA0004136029870000021
Figure FDA0004136029870000031
Figure FDA0004136029870000041
Figure FDA0004136029870000051
Figure FDA0004136029870000061
Figure FDA0004136029870000071
2. the use of claim 1, wherein the bacterium that produces neo-deli-beta-lactamase-1 is a gram-negative bacterium that produces neo-deli-beta-lactamase-1.
3. The use of claim 2, wherein the gram-negative bacterium that produces neodrela- β -lactamase-1 is klebsiella pneumoniae, escherichia coli, enterobacter cloacae, acinetobacter baumannii, or citrobacter.
4. Use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament as a novel deli-beta-lactamase inhibitor, wherein:
the compound is selected from:
Figure FDA0004136029870000072
Figure FDA0004136029870000081
Figure FDA0004136029870000091
Figure FDA0004136029870000101
Figure FDA0004136029870000111
Figure FDA0004136029870000121
Figure FDA0004136029870000131
5. use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in antibacterial, wherein: the antibacterial is against bacteria producing novel deltoid metal-beta-lactamase-1, and the compound is selected from the group consisting of:
Figure FDA0004136029870000141
Figure FDA0004136029870000151
Figure FDA0004136029870000161
Figure FDA0004136029870000171
Figure FDA0004136029870000181
Figure FDA0004136029870000191
6. the use of claim 5, wherein the antibacterial is bactericidal or bacteriostatic activity.
7. The use according to claim 5, wherein
The bacteria producing novel Derilmetal-beta-lactamase-1 are gram-negative bacteria producing novel Derilmetal-beta-lactamase-1.
8. The use of claim 7, wherein the gram-negative bacterium that produces neodymite- β -lactamase-1 is klebsiella pneumoniae, escherichia coli, enterobacter cloacae, acinetobacter baumannii, or citrobacter.
9. Use of a pharmaceutical composition for the preparation of a medicament for the prevention and/or treatment of infections caused by bacteria, or
Use in the preparation of a medicament for use in antibacterial, or
The use in the manufacture of a medicament as a novel Deril metal-beta-lactamase inhibitor,
wherein: the pharmaceutical composition contains a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient,
the bacteria are bacteria producing novel Derilmetal-beta-lactamase-1,
the antibacterial is bacteria for resisting the production of new Derilmetal-beta-lactamase-1,
the compound is selected from:
Figure FDA0004136029870000201
Figure FDA0004136029870000211
Figure FDA0004136029870000221
Figure FDA0004136029870000231
Figure FDA0004136029870000241
Figure FDA0004136029870000251
Figure FDA0004136029870000261
10. the use of claim 9, wherein the antibacterial is bactericidal or bacteriostatic activity.
11. The use of claim 9, wherein the bacterium that produces neo-deli-beta-lactamase-1 is a gram-negative bacterium that produces neo-deli-beta-lactamase-1.
12. The use of claim 11, wherein the new deli-beta-lactamase-1-producing gram-negative bacterium is klebsiella pneumoniae, escherichia coli, enterobacter cloacae, acinetobacter baumannii, or citrobacter.
13. The use of claim 9, wherein the composition further comprises a β -lactam antibiotic.
14. The use of claim 13, wherein the β -lactam antibiotic is selected from the group consisting of: penicillins, cephalosporins, carbapenems, thiomycins, monobactams or oxacephems.
15. The use of claim 14, wherein:
the penicillins are selected from: penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, mexillin, temoxicillin, oxacillin, dicloxacillin, flucloxacillin, amoxicillin, pivoxillin, carbenicillin, sulbenicillin, furbenicillin, azlocillin, ticarcillin, piperacillin;
the cephalosporins are selected from: cefazolin, cefradine, cefprozil, cefuroxime, cefotiam, cefaclor, cefuroxime, cefprozil, ceftioxime, ceftriaxone, ceftazidime, cefoperazone, cefixime, cefpodoxime proxetil, ceftaroline, ceftolterone, cefalotin, ceftizoxime, cefpirome, cefamandole, cefpirate;
the cephalosporins are selected from: cefoxitin, cefmetazole and cefminox;
The carbapenems are selected from: meropenem, imipenem, panipenem, ertapenem, faropenem, biapenem, doripenem, ai Papei south;
the monocyclic β -lactams are selected from: aztreonam, carumonam;
the oxacephem is selected from: laroxb and flomoxef.
16. The use of a compound or a pharmaceutically acceptable salt thereof in combination with a beta-lactam antibiotic for the manufacture of a medicament for the prophylaxis and/or treatment of infections caused by bacteria, or for the manufacture of a medicament for use in antibacterial,
wherein:
the bacterium is a bacterium producing neodelbrueck-beta-lactamase-1, the antibacterial is a bacterium resistant to neodelbrueck-beta-lactamase-1, and the compound is selected from the group consisting of:
Figure FDA0004136029870000281
Figure FDA0004136029870000291
Figure FDA0004136029870000301
Figure FDA0004136029870000311
Figure FDA0004136029870000321
Figure FDA0004136029870000331
17. the use of claim 16, wherein the antibacterial is bactericidal or bacteriostatic activity.
18. The use of claim 16, wherein the bacterium that produces neo-deli-beta-lactamase-1 is a gram-negative bacterium that produces neo-deli-beta-lactamase-1.
19. The use of claim 18, wherein the new deli-beta-lactamase-1-producing gram-negative bacterium is klebsiella pneumoniae, escherichia coli, enterobacter cloacae, acinetobacter baumannii, or citrobacter.
20. The use of claim 16, wherein the β -lactam antibiotic is selected from the group consisting of: penicillins, cephalosporins, carbapenems, thiomycins, monobactams and oxacephems.
21. The use of claim 20, wherein:
the penicillins are selected from: penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, mexillin, temoxicillin, oxacillin, dicloxacillin, flucloxacillin, amoxicillin, pivoxillin, carbenicillin, sulbenicillin, furbenicillin, azlocillin, ticarcillin, piperacillin;
the cephalosporins are selected from: cefazolin, cefradine, cefprozil, cefuroxime, cefotiam, cefaclor, cefuroxime, cefprozil, ceftioxime, ceftriaxone, ceftazidime, cefoperazone, cefixime, cefpodoxime proxetil, ceftaroline, ceftolterone, cefalotin, ceftizoxime, cefpirome, cefamandole, cefpirate;
the cephalosporins are selected from: cefoxitin, cefmetazole and cefminox;
The carbapenems are selected from: meropenem, imipenem, panipenem, ertapenem, faropenem, biapenem, doripenem, ai Papei south;
the monocyclic β -lactams are selected from: aztreonam, carumonam;
the oxacephem is selected from: laroxb and flomoxef.
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