High Content Screening Identifies Decaprenyl-Phosphoribose 2′ Epimerase as a Target for Intracellular Antimycobacterial Inhibitors
Thierry ChristopheMary JacksonHee Kyoung JeonDenis FenisteinMonica Contreras-DomínguezJaeseung KimAuguste GenovesioJean‐Philippe CarralotFanny EwannEun Hye KimSae Yeon LeeSun‐Hee KangMin Jung SeoEun Jung ParkHenrieta ŠkovierováHà PhạmGiovanna RiccardiJi Youn NamLaurent MarsollierMarie KempfMarie‐Laure Joly‐GuillouTaegwon OhWon Kyung ShinZaesung NoUlf NehrbassRoland BroschStewart T. ColePriscille Brodin
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Abstract:
A critical feature of Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB), is its ability to survive and multiply within macrophages, making these host cells an ideal niche for persisting microbes. Killing the intracellular tubercle bacilli is a key requirement for efficient tuberculosis treatment, yet identifying potent inhibitors has been hampered by labor-intensive techniques and lack of validated targets. Here, we present the development of a phenotypic cell-based assay that uses automated confocal fluorescence microscopy for high throughput screening of chemicals that interfere with the replication of M. tuberculosis within macrophages. Screening a library of 57,000 small molecules led to the identification of 135 active compounds with potent intracellular anti-mycobacterial efficacy and no host cell toxicity. Among these, the dinitrobenzamide derivatives (DNB) showed high activity against M. tuberculosis, including extensively drug resistant (XDR) strains. More importantly, we demonstrate that incubation of M. tuberculosis with DNB inhibited the formation of both lipoarabinomannan and arabinogalactan, attributable to the inhibition of decaprenyl-phospho-arabinose synthesis catalyzed by the decaprenyl-phosphoribose 2' epimerase DprE1/DprE2. Inhibition of this new target will likely contribute to new therapeutic solutions against emerging XDR-TB. Beyond validating the high throughput/content screening approach, our results open new avenues for finding the next generation of antimicrobials.Keywords:
Antimycobacterial
High-Content Screening
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The compounds studied are propylthiadiazoloquinazoline derivatives, tryptanthrin analogs. Tryptantrin and its derivatives were found to have different antimycobacterial activity in vitro and in vivo. This series of experiments is devoted to the study of antimycobacterial activity of three propylthiadiazoloquinazoline derivatives obtained in the laboratory of organic synthesis and Biopharmaceutics of the Institute of Chemistry of the Academy of Sciences in Moldova using a non-tuberculous strain of Mycobacterium intracellulare, which is a part of the Mycobacterium avium complex (MAC). Species of the MAC are one of the main pathogen types causing mycobacteriosis. In this regard, propylthiadiazoloquinazoline derivatives are of interest for a comprehensive study as a potential antimycobacterial drug. To study antimycobacterial activity the method of dilutions in a dense nutrient medium of Middlebrook 7H9 broth with glycerol in Petri dishes was used. To assess antimycobacterial activity visual assessment of M. intracellulare growth in a solid nutrient medium was used. It is shown that the compounds studied inhibit M. Intracellulare growth. The most active compound was compound № 1 - 2-mercapto-5H-[1,3,4]-thiadiazolo-[2,3-b]-quinazoline-5-one.
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A series of 14 hydrochlorides of piperidinylethyl esters of orthosubstituted phenylcarbamic acids were evaluated for in vitro antimycobacterial activity against the strains of Mycobacterium tuberculosis, Mycobactenum kansasii and Mycobactenum avium. In vitro antimycobacterial activrty becomes higher with increasing hydrophobicity of the substituents. The alkoxy group is not necessary in order for the basic ethyl esters of phenylcarbamic acids to display antimycobacterial activity.
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According to our previous study 29 derivatives of 2-hydroxy-3-(4-phenylpiperazin-1-yl)-propylphenylcarbamates were tested for in vitro antimycobacterial activity against potential pathogenic strains Mycobacterium kansasii and Mycobacterium avium. The variations in group of compounds were by the substitution on phenyl rings. The Free-Wilson method was used to evaluate structure-antimycobacterial activity relationships. The advantage of compounds under study is in the activity against M. kansasii.
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Білім берy қоғaмның экономикaлық дaмyының негізі, әлеyметтік тұрaқтылықтың фaкторлaрының бірі, хaлықтың рyхaни-aдaмгершілік әлеyетінің және интеллектyaлдық өсyінің қaйнaр көзі ретінде бaрлық yaқыттaрдa тaптырмaс құндылық болып есептеліп келеді. Aл қaзіргідей aдaм кaпитaлын қaлыптaстырy мен дaмытy мәселесін шешy негізгі міндет ретінде қaрaстырылaтын зaмaндa хaлықтың білімдік қaжеттіліктері өсіп, жоғaры, ортa aрнayлы, кәсіби қосымшa білім aлyғa үміткерлер сaны aртa түсyде. Бұғaн жayaп ретінде білім берy ұйымдaрының сaлaлaнyы aртып, әртүрлі типтегі оқy орындaрының сaны aртyдa, білім берyдің инфрaқұрылымы, бaсқaрy формaлaры, әдістемелік, ғылыми қызмет түрлері дaмyдa. Олaрды білім aлyшылaрдың жеке сұрaныстaры мен мүмкіндіктеріне бaғыттay күшейтілyде. Осығaн орaй білімнің сaпaсынa қойылaтын тaлaптaр aртып, бұл сaлaның әлеyметпен өзaрa әрекеттестігіне негізделген құрылымдық – қызметтік дaмyының көкейтестілігі aртyдa. Мaқaлaдa «серіктестік», «әлеyметтік серіктестік», «білімдегі әлеyметтік серіктестік» ұғым- дaрының мәні aшылып, олaрдың қaлыптaсy және дaмy үрдісіне шолy жaсaлaды, жоғaры оқy орындaрындa педaгогтaрды дaярлayдa әлеyметтік серіктестердің әлеyетін пaйдaлaнyдa бaсшылыққa aлынaтын ұстaнымдaр мен тиімді жолдaры сипaттaлaды. Түйін сөздер: серіктестік, әлеyметтік серіктестік, білімдегі әлеyметтік серіктестік, бірлескен әрекет ұстaнымдaры, әлеуметтік серіктестік әлеуеті. Обрaзовaние является основой экономического рaзвития обществa, одним из фaкторов социaль- ной стaбильности, источником дyховно-нрaвственного потенциaлa и интеллектyaльного ростa людей и во все временa считaлось незaменимой ценностью. И в нaстоящее время, когдa решение проблемы формировaния и рaзвития человеческого кaпитaлa рaссмaтривaется кaк основнaя зaдaчa, рaстyт обрaзовaтельные потребности людей, yвеличивaется количество желaющих полyчить высшее, среднее, специaльное, профессионaльное дополнительное обрaзовaние. В ответ нa это yсиливaется рaзветвленность обрaзовaтельных оргaнизaций, yвеличивaется количество обрaзовaтельных оргaни- зaций рaзличного типa, рaзвивaются инфрaстрyктyрa обрaзовaния, формы yпрaвления, методическaя и нayчнaя деятельность. Yсиливaется их ориентaция нa индивидyaльные потребности и возможности обyчaющихся. В связи с этим повышaются требовaния к кaчествy обрaзовaния, возрaстaет знaчение стрyктyрно-фyнкционaльного рaзвития этой сферы нa основе взaимодействия с обществом. В стaтье рaскрывaется знaчение понятий «пaртнерство», «социaльное пaртнерство», «социaльное пaртнерство в обрaзовaнии», рaссмaтривaется процесс их стaновления и рaзвития, описывaются рyко- водящие принципы и эффективные способы использовaния потенциaлa социaльных пaртнеров в подготовке педaгогических кaдров в высших yчебных зaведениях. Ключевые словa: партнерство, социaльное пaртнерство, социaльное пaртнерство в обрaзовaнии, принципы совместного действия, поненциал социального партнерство. Education is the basis of the economic development of society, one of the factors of social stability, a source of spiritual and moral potential and intellectual growth of people and has always been considered an irreplaceable value. And at the present time, when the solution of the problem of the formation and development of human capital is considered as the main task, the educational needs of people are growing, the number of people wishing to receive higher, secondary, special, professional additional education is increasing. In response to this, the branching of educational organizations is increasing, the number of educational organizations of various types is increasing, the infrastructure of education, forms of management, methodological and scientific activities are developing. Their focus on the individual needs and capabilities of students is increasing. In this regard, the requirements for the quality of education are increasing, the importance of the structural and functional development of this sphere on the basis of interaction with society is increasing. The article reveals the meaning of the concepts of "partnership", "social partnership", "social partnership in education", examines the process of their formation and development, describes the guidelines and effective ways to use the potential of social partners in the training of teachers in higher educational institutions. Keywords: partnership, social partnership, social partnership in education, principles of joint action, the potential of social partnership.
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Antimycobacterial effects of thiosemicarbazones were discovered in the late 1940s. The best known representative of these compounds is thioacetazone that has been used in the therapy of tuberculosis since the turn of the 1940s and 1950s. At present, it is used only rarely since it exhibits severe side effects. This paper deals with the antimycobacterial effects of thiosemicarbazones and N,N-dimethylthiosemicarbazones derived from 5-alkyl-2-acetylpyrazines. Some of these compounds displayed high inhibition of the growth of Mycobacterium tuberculosis H37Rv, but were excluded from the in vivo studies due to their cytotoxic effects. Nonetheless, they can be used as model compounds for studying the mechanisms of antimycobacterial action of thiosemicarbazones.
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Tuberculosis constitutes a serious public health problem because it has multi-resistant forms that require treatment that is both difficult and extensive. There is a need to develop new antimycobacterial compounds, and plants represent a source of therapeutic resources. This study analyzed antimycobacterial action in eight extracts from plants found in the Brazilian Cerrado. The results showed significant inhibitory concentrations in relation to Mycobacterium tuberculosis, especially from the extracts of Apuleia molaris and Ouratea spectabilis, both of which presented reduced cytotoxic effects. Fractionation revealed a hexane fraction of A. molaris with significant and promising activity regarding future in vivo assays.
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