3,5-Dinitrobenzylsulfanyl tetrazoles and 1,3,4-oxadiazoles, previously identified as having high in vitro activities against both replicating and nonreplicating mycobacteria and favorable cytotoxicity and genotoxicity profiles were investigated. First we demonstrated that these compounds act in a deazaflavin-dependent nitroreduction pathway and thus require a nitro group for their activity. Second, we confirmed the necessity of both nitro groups for antimycobacterial activity through extensive structure-activity relationship studies using 32 structural types of analogues, each in a five-membered series. Only the analogues with shifted nitro groups, namely, 2,5-dinitrobenzylsulfanyl oxadiazoles and tetrazoles, maintained high antimycobacterial activity but in this case mainly as a result of DprE1 inhibition. However, these analogues also showed increased toxicity to the mammalian cell line. Thus, both nitro groups in 3,5-dinitrobenzylsulfanyl-containing antimycobacterial agents remain essential for their high efficacy, and further efforts should be directed at finding ways to address the possible toxicity and solubility issues, for example, by targeted delivery.

• MeSH
• antituberkulotika farmakologie   chemie   MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis * MeSH
• nitroreduktasy MeSH
• oxadiazoly farmakologie   chemie   MeSH
• savci MeSH
• tetrazoly farmakologie   chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The war in Ukraine has led to significant migration to neighboring countries, raising public health concerns. Notable tuberculosis (TB) incidence rates in Ukraine emphasize the immediate requirement to prioritize approaches that interrupt the spread and prevent new infections. METHODS: We conducted a prospective genomic surveillance study to assess migration's impact on TB epidemiology in the Czech Republic and Slovakia. Mycobacterium tuberculosis isolates from Ukrainian war refugees and migrants, collected from September 2021 to December 2022 were analyzed alongside 1574 isolates obtained from Ukraine, the Czech Republic, and Slovakia. RESULTS: Our study revealed alarming results, with historically the highest number of Ukrainian tuberculosis patients detected in the host countries. The increasing number of cases of multidrug-resistant TB, significantly linked with Beijing lineage 2.2.1 (p < 0.0001), also presents substantial obstacles to control endeavors. The genomic analysis identified the three highly related genomic clusters, indicating the recent TB transmission among migrant populations. The largest clusters comprised war refugees diagnosed in the Czech Republic, TB patients from various regions of Ukraine, and incarcerated individuals diagnosed with pulmonary TB specialized facility in the Kharkiv region, Ukraine, pointing to a national transmission sequence that has persisted for over 14 years. CONCLUSIONS: The data showed that most infections were likely the result of reactivation of latent disease or exposure to TB before migration rather than recent transmission occurring within the host country. However, close monitoring, appropriate treatment, careful surveillance, and social support are crucial in mitigating future risks, though there is currently no evidence of local transmission in EU countries.

• MeSH
• dospělí MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• molekulární epidemiologie * MeSH
• multirezistentní tuberkulóza epidemiologie   MeSH
• Mycobacterium tuberculosis * genetika   izolace a purifikace   MeSH
• osoby s přechodným pobytem a migranti * statistika a číselné údaje   MeSH
• ozbrojené konflikty MeSH
• prospektivní studie MeSH
• tuberkulóza * epidemiologie   přenos   MeSH
• uprchlíci * statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH
• Ukrajina MeSH

Nová doporučení navazují na Standard léčebného plánu z roku 2012(1) a na vydání speciálního čísla Česko-slovenské pediatrie z roku 2016 věnovaného problematice tuberkulózy (TB).(2) V předkládaném dokumentu reflektujeme nová doporučení Světové zdravotnické organizace (WHO),(3) která dlouhodobě hledá nové strategie pro optimální léčbu dětských a dorostových pacientů, neboť celosvětově onemocní TB ročně více než 10 milionů lidí, z toho 1,2 milionu dětí.(4) V České republice zůstává TB vzácným onemocněním s incidencí 3,6 : 100 000 v roce 2022.(5) Dětská TB odráží trend dospělé TB. Mezi roky 2010–2020 byl trend klesající. Ani změna očkovací strategie v roce 2010 tento trend nezměnila.(6) Od roku 2021 pozorujeme mírný nárůst dětských pacientů s TB. V roce 2023 onemocnělo TB 29 dětí (obr. 1). Nárůst dětských případů TB, včetně forem rezistentních na léčbu, zvyšuje nárok na aktualizaci doporučení pro diagnostiku a léčbu v souladu se světovými trendy. Hlavní změny v doporučeném postupu se týkají zejména zkrácení léčby nekomplikované TB u dětí ve věku 3–16 let na 4 měsíce. Dále jsou zde nově definované skupiny TB rezistentní na léčbu (drug resistant – DR) a nové strategie její léčby, jejíž součástí je podávání bedaquilinu a delamanidu. Inovativní je také zavedení TB preventivní terapie u kontaktů s DR-TB.

The new recommendations are a follow-up to the 2012 Standard treatment guidelines(1) and the 2016 special issue of Czech-Slovak Paediatrics dedicated to tuberculosis (TB).(2) The present document reflects the new recommendations(3) of the World Health Organization (WHO), which has long been seeking new strategies for optimal treatment of paediatric and adolescent patients, as more than 10 million people worldwide develop TB annually, including 1.2 million children.(4) In the Czech Republic, TB remains a rare disease, with an incidence of 3.6/100,000 in 2022.(5) Childhood TB mirrors the trend of adult TB. Between 2010–2020, the trend was downward. Even the change in vaccination strategy in 2010 did not change this trend.(6) From 2021, we observe a slight increase in paediatric TB cases. In 2023, 29 children developed TB (Figure 1). The increase in paediatric TB cases, including treatment-resistant forms, makes it imperative to update recommendations for diagnosis and treatment in line with global trends. In particular, the main changes to the recommended approach relate to shortening treatment of uncomplicated TB in children aged 3-16 years to 4 months. There are also newly defined groups of drug-resistant (DR) TB and a new strategy for their treatment, which includes the administration of bedaquiline and delamanid. The introduction of TB preventive therapy for contacts of DR-TB is also innovative.

• MeSH
• antituberkulotika terapeutické užití   MeSH
• BCG vakcína MeSH
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• multirezistentní tuberkulóza klasifikace   terapie   MeSH
• Mycobacterium tuberculosis imunologie   izolace a purifikace   patogenita   MeSH
• tuberkulóza * diagnóza   prevence a kontrola   terapie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• směrnice pro lékařskou praxi MeSH
• Geografické názvy
• Česká republika MeSH

Tuberkulózni pacienti vyžadujúci akútnu intenzívnu starostlivosť tvoria asi 1–3 % zo všetkých pacientov s tuberkulózou. Respiračné zlyhanie bola najčastejšia príčina príjmu pacientov na intenzívne oddelenie v našej retrospektívnej analýze súboru pacientov (n = 36). Vstupná leukocytóza, hypoalbuminémia a SOFA skóre predstavujú významné prediktívne faktory určujúce prežívanie pacientov. Protektívna ventilačná stratégia pacientov s nehomogénnym pľúcnym parenchýmom pri rozvinutej infekcii tuberkulózy je podobná ako pri manažmente ARDS. Cielená terapia býva častokrát oneskorená pre netypický priebeh tuberkulózneho ochorenia a jeho foriem. Intravenózna antituberkulózna terapia na intenzívnej jednotke vykazuje lepšie prežívanie pacientov. Svetovo narastajúci počet pacientov s multirezistentnou tuberkulózou (MDR-TB) a extenzívne rezistentnou tuberkulózou (XDR-TB) predstavuje zvýšené riziko aj pre nemocničný personál.

x

• MeSH
• antituberkulotika terapeutické užití   MeSH
• hypoalbuminemie krev   MeSH
• leukocytóza krev   MeSH
• lidé MeSH
• Mycobacterium tuberculosis patogenita   MeSH
• péče o pacienty v kritickém stavu * MeSH
• přenos infekce z pacienta na zdravotnického pracovníka prevence a kontrola   MeSH
• respirační insuficience etiologie   terapie   MeSH
• tuberkulóza * diagnóza   farmakoterapie   mikrobiologie   mortalita   MeSH
• vyhodnocení orgánové dysfunkce MeSH
• Check Tag
• lidé MeSH

• MeSH
• antituberkulotika * terapeutické užití   farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti * MeSH
• multirezistentní tuberkulóza * farmakoterapie   diagnóza   mikrobiologie   MeSH
• Mycobacterium tuberculosis účinky léků   genetika   MeSH
• rifampin * terapeutické užití   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• komentáře MeSH
• Geografické názvy
• Evropa MeSH

Mycobacterium tuberculosis (Mtb) remains a major threat worldwide, although only a fraction of infected individuals develops tuberculosis (TB). TB susceptibility is shaped by multiple genetic factors, and we performed comparative immunological analysis of two mouse strains to uncover relevant mechanisms underlying susceptibility and resistance. C57BL/6 mice are relatively TB-resistant, whereas I/St mice are prone to develop severe TB, partly due to the MHC-II allelic variant that shapes suboptimal CD4+ T cell receptor repertoire. We investigated the repertoires of lung-infiltrating helper T cells and B cells at the progressed stage in both strains. We found that lung CD4+ T cell repertoires of infected C57BL/6 but not I/St mice contained convergent TCR clusters with functionally confirmed Mtb specificity. Transcriptomic analysis revealed a more prominent Th1 signature in C57BL/6, and expression of pro-inflammatory IL-16 in I/St lung-infiltrating helper T cells. The two strains also showed distinct Th2 signatures. Furthermore, the humoral response of I/St mice was delayed, less focused, and dominated by IgG/IgM isotypes, whereas C57BL/6 mice generated more Mtb antigen-focused IgA response. We conclude that the inability of I/St mice to produce a timely and efficient anti-Mtb adaptive immune responses arises from a suboptimal helper T cell landscape that also impacts the humoral response, leading to diffuse inflammation and severe disease.

• MeSH
• adaptivní imunita * genetika   MeSH
• B-lymfocyty imunologie   MeSH
• genetická predispozice k nemoci * MeSH
• modely nemocí na zvířatech MeSH
• Mycobacterium tuberculosis * imunologie   MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• plíce imunologie   patologie   MeSH
• receptory antigenů T-buněk genetika   imunologie   MeSH
• tuberkulóza * imunologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Bacteria have evolved structured RNAs that can associate with RNA polymerase (RNAP). Two of them have been known so far-6S RNA and Ms1 RNA but it is unclear if any other types of RNAs binding to RNAP exist in bacteria. To identify all RNAs interacting with RNAP and the primary σ factors, we have established and performed native RIP-seq in Bacillus subtilis, Corynebacterium glutamicum, Streptomyces coelicolor, Mycobacterium smegmatis and the pathogenic Mycobacterium tuberculosis. Besides known 6S RNAs in B. subtilis and Ms1 in M. smegmatis, we detected MTS2823, a homologue of Ms1, on RNAP in M. tuberculosis. In C. glutamicum, we discovered novel types of structured RNAs that associate with RNAP. Furthermore, we identified other species-specific RNAs including full-length mRNAs, revealing a previously unknown landscape of RNAs interacting with the bacterial transcription machinery.

• MeSH
• Bacillus subtilis genetika   metabolismus   MeSH
• bakteriální proteiny * metabolismus   genetika   MeSH
• bakteriální RNA * metabolismus   genetika   MeSH
• Corynebacterium glutamicum genetika   metabolismus   MeSH
• DNA řízené RNA-polymerasy * metabolismus   genetika   MeSH
• genetická transkripce MeSH
• konformace nukleové kyseliny MeSH
• Mycobacterium smegmatis genetika   metabolismus   enzymologie   MeSH
• Mycobacterium tuberculosis genetika   metabolismus   MeSH
• nekódující RNA MeSH
• regulace genové exprese u bakterií MeSH
• sigma faktor * metabolismus   genetika   MeSH
• Streptomyces coelicolor genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Authors present a pilot study of the development of innovative flow cytometry-based assay with a potential for use in tuberculosis diagnostics. Currently available tests do not provide robust discrimination between latent tuberculosis infection (TBI) and tuberculosis disease (TB). The desired application is to distinguish between the two conditions by evaluating the production of a combination of three cytokines: IL-2 (interleukin-2), IFNɣ (interferon gamma) and TNFɑ (tumor necrosis factor alpha) in CD4+ and CD8+ T cells. The study was conducted on 68 participants, divided into two arms according to age (paediatric and adults). Each arm was further split into three categories (non-infection (NI), TBI, TB) based on the immune reaction to Mycobacterium tuberculosis (M.tb) after a close contact with pulmonary TB. Each blood sample was stimulated with specific M.tb antigens present in QuantiFERON tubes (TB1 and TB2). We inferred TBI or TB based on the predominant cytokine response of the CD4+ and/or CD8+ T cells. Significant differences were detected between the NI, TBI and the TB groups in TB1 in the CD4+TNFɑ+parameter in children. Along with IL-2, TNFɑ seems to be the most promising diagnostic marker in both CD4+and CD8+ T cells. However, more detailed analyses on larger cohorts are needed to confirm the observed tendencies.

• MeSH
• antigeny bakteriální imunologie   MeSH
• biologické markery krev   MeSH
• CD4-pozitivní T-lymfocyty * imunologie   MeSH
• CD8-pozitivní T-lymfocyty * imunologie   MeSH
• cytokiny krev   metabolismus   MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• dospělí MeSH
• interferon gama * krev   imunologie   MeSH
• interleukin-2 * krev   MeSH
• latentní tuberkulóza * diagnóza   imunologie   mikrobiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Mycobacterium tuberculosis * imunologie   MeSH
• pilotní projekty MeSH
• plicní tuberkulóza diagnóza   imunologie   mikrobiologie   krev   MeSH
• prediktivní hodnota testů MeSH
• předškolní dítě MeSH
• průtoková cytometrie * metody   MeSH
• senioři MeSH
• test pomocí interferonu gama metody   MeSH
• TNF-alfa krev   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring. This series brought two new compounds (21: R = 2-F, 4-Cl and 22: R = 2-F, 4-Br) with in vitro activity against Mycobacterium tuberculosis H37Rv as well as multidrug-resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25 μg/mL. The lactone-type derivatives 4H-pyrazino[2,3-d][1,3]oxazin-4-ones (Series-3) were inactive, but solvent stability studies of compound 29 indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).

• MeSH
• aminoacyl-tRNA-synthetasy antagonisté a inhibitory   metabolismus   MeSH
• antituberkulotika * farmakologie   chemie   chemická syntéza   MeSH
• inhibitory enzymů farmakologie   chemie   chemická syntéza   MeSH
• mikrobiální testy citlivosti * MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis * účinky léků   enzymologie   MeSH
• pyraziny farmakologie   chemie   chemická syntéza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 μg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 μM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

• MeSH
• antituberkulotika farmakologie   chemie   MeSH
• bakteriální proteiny metabolismus   MeSH
• chinoliny * farmakologie   MeSH
• isatin * farmakologie   MeSH
• lidé MeSH
• mikrobiální testy citlivosti MeSH
• Mycobacterium tuberculosis * MeSH
• oxidoreduktasy metabolismus   MeSH
• protein přenášející acyl farmakologie   MeSH
• simulace molekulového dockingu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH