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The constant progress of genomics and the establishment of new functional tests have paved the way for identifying monogenic defects conferring a selective predisposition to infections by certain microbes as a new type of inborn errors of immunity (IEIs). Mendelian susceptibility to mycobacterial diseases (MSMD) is the most characterized of these IEIs, with 36 different disorders found in 20 distinct genes (IFNGR1, IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1, TYK2, IRF8, IRF1, CYBB, JAK1, RORC, NEMO, and SPPL2A) over the last 20 years. MSMD confers a selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guerin (BCG) vaccines and various environmental mycobacteria in patients, primarily children, without classical immune defects. These patients may also present severe forms of tuberculosis, and about half of them might develop non-typhoidal salmonellosis. In some cases, patients also suffer from chronic mucocutaneous candidiasis (CMC), while in others, patients also present severe viral, parasitic, fungal, and/or bacterial diseases. Despite this clinical and genetic heterogeneity, almost all genetic etiologies of MSMD alter the interferon-gamma (IFN-γ)- mediated immunity by impairing or abolishing IFN-γ production or the response to this cytokine. It was proven that the human IFN-γ level is a quantitative trait that defines the outcome of mycobacterial infection. The study of these monogenic defects contributes to understanding the molecular mechanism of mycobacterial diseases in humans and to the development of new diagnostic and therapeutic approaches to improve care and prognosis. For example, MSMD patients with impaired production of IFN-γ may benefit from injections of human recombinant IFN-γ, while for patients with abolished response to this cytokine, hematopoietic stem cell transplantation (HSCT) and promising gene therapy are the only current therapeutic options. These discoveries also bridge the gap between simple Mendelian inheritance and complex human genetics.

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Introduction: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare inherited condition characterized by selective susceptibility to weakly virulent mycobacteria, such as substrains of the bacille Calmette-Guérin (BCG) vaccine and different environmental mycobacteria. Case presentation: A 7-year-old Sudanese boy was referred to the immunology clinic with a suspected diagnosis of MSMD. This followed multiple presentations with disseminated tuberculosis and typhoid fever. Genetic testing surprisingly revealed pathogenic homozygous variants in IL12RB1 Exon 9, c.913A>T (p. Lys305*) in both the patient and his father, with a completely healthy asymptomatic carrier mother who is not blood related to the patient's father. Conclusion: It is challenging to diagnose MSMD, especially in developing countries where health systems are poor and have limited resources. Family history and genetic tests may help in early MSMD treatment and avoiding disease complications.

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Background: Inborn errors of IL-12/IL-23-IFNγ immunity underlie Mendelian susceptibility to mycobacterial diseases (MSMD), a group of immunodeficiencies characterized by a highly selective susceptibility to weakly virulent strains of mycobacteria, such as non-tuberculous mycobacteria (NTM) and bacillus Calmette-Guérin (BCG). Cutaneous mycobacterial infections are common in MSMD and may represent a red flag for this immunodeficiency. Objectives: We present a case series of four paediatric patients with MSMD, specifically with IFNγR1 and STAT1 deficiencies, and cutaneous NTM/BCG infections to increase awareness of this immunodeficiency, which may, in some cases, be intercepted by the dermatologist and thus timely referred to the immunologist. Materials & Methods: Clinical, laboratory and genetic investigations of the four paediatric patients with MSMD are presented. Results: All four presented patients experienced early complications after BCG vaccination. Two patients suffered recurrent mycobacteriosis, one patient experienced delayed BCG reactivation, and one patient died of disseminated avian mycobacteriosis. The dermatological manifestation in these patients included destructive nasal ulcerations, scrofuloderma of various sites and lupus vulgaris. All patients had a normal basic immune phenotype. Conclusion: The presented cases demonstrate that NTM/BCG infections in otherwise seemingly immunocompetent patients should raise suspicion of MSMD. This is of utmost importance as specific therapeutic approaches, such as IFNγ treatment or haematopoietic stem cell transplantation, may be employed to improve the disease outcome.

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OBJECTIVE: To report the clinical and imaging characteristics of BCG-osteomyelitis, and compare them with those of pyogenic osteomyelitis. MATERIALS AND METHODS: Clinical and imaging findings were retrospectively evaluated in 14 children with BCG osteomyelitis, including 3 with Mendelian susceptibility to mycobacterial diseases (MSMD), and in 40 children with pyogenic osteomyelitis, using Fisher exact and Mann-Whitney U tests. RESULTS: BCG-osteomyelitis was an indolent inflammatory disease of young children (mean age 15.5 months). Immunocompetent patients came to medical attention over months after vaccination, while patients with MSMD much earlier (the average time lapse: 13.7 vs. 5.0 months). The former manifested with a slowly progressive, painless mass with only mildly increased acute-phase reactants, while the latter started with lymphadenitis with significant inflammatory reactions and later developed osteomyelitis. These clinical scenarios contrasted with acute febrile illness in pyogenic osteomyelitis. The imaging findings were identical in both immunocompetent and MSMD groups; however, the former showed monoostotic involvement, while the latter polyostotic affliction. The typical imaging finding of BCG-osteomyelitis comprises a large intraosseous abscess with modest reactive edema commonly associated with transphyseal extension from the metaphysis to the epiphysis, contrasting with the manifestation of pyogenic osteomyelitis; size of abscess (p=0.028), pattern of abscess extension (p<0.001), and extent of surrounding edema (p<0.001). CONCLUSIONS: BCG-osteomyelitis should be suspected in children under 2 years of age with insidious osteomyelitis, accompanied with characteristic imaging findings. Polyostotic BCG osteomyelitis is highly suggestive of MSMD. Awareness of the distinctive features of BCG-osteomyelitis enables the early diagnosis and timely therapeutic intervention.

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BACKGROUND: Patients with Mendelian susceptibility to mycobacterial disease (MSMD) experience recurrent and/or persistent infectious diseases associated with poorly virulent mycobacteria. Multifocal osteomyelitis is among the representative manifestations of MSMD. The frequency of multifocal osteomyelitis is especially high in patients with MSMD etiologies that impair cellular response to IFN-γ, such as IFN-γR1, IFN-γR2, or STAT1 deficiency. OBJECTIVES: This study sought to characterize the mechanism underlying multifocal osteomyelitis in MSMD. METHODS: GM colonies prepared from bone marrow mononuclear cells from patients with autosomal dominant (AD) IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 gain of function (GOF) and from healthy controls were differentiated into osteoclasts in the presence or absence of IFN-γ. The inhibitory effect of IFN-γ on osteoclastogenesis was investigated by quantitative PCR, immunoblotting, tartrate-resistant acid phosphatase staining, and pit formation assays. RESULTS: Increased osteoclast numbers were identified by examining the histopathology of osteomyelitis in patients with AD IFN-γR1 deficiency or AD STAT1 deficiency. In the presence of receptor activator of nuclear factor kappa-B ligand and M-CSF, GM colonies from patients with AD IFN-γR1 deficiency, AD STAT1 deficiency, or STAT1 GOF differentiated into osteoclasts, similar to GM colonies from healthy volunteers. IFN-γ concentration-dependent inhibition of osteoclast formation was impaired in GM colonies from patients with AD IFN-γR1 deficiency or AD STAT1 deficiency, whereas it was enhanced in GM colonies from patients with STAT1 GOF. CONCLUSIONS: Osteoclast differentiation is increased in AD IFN-γR1 deficiency and AD STAT1 deficiency due to an impaired response to IFN-γ, leading to excessive osteoclast proliferation and, by inference, increased bone resorption in infected foci, which may underlie multifocal osteomyelitis.

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Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled. Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions. Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed. Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection. Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.

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Summary: We characterized Mycobacterium bovis BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. Background: We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG infection after neonatal vaccination (BCG-vaccine). Distinct M. bovis BCG-vaccine derived clinical strains were recovered from the patient's lungs and brain. Methods: BCG strains were phenotypically (growth, antibiotic susceptibility, lipid) and genetically (whole genome sequencing) characterized. Mycobacteria cell infection models were used to assess apoptosis, necrosis, cytokine release, autophagy, and JAK-STAT signaling. Results: Clinical isolates BCG-brain and BCG-lung showed distinct Rv0667 rpoB mutations conferring high- and low-level rifampin resistance; the latter displayed clofazimine resistance through Rv0678 gene (MarR-like transcriptional regulator) mutations. BCG-brain and BCG-lung showed mutations in fadA2, fadE5, and mymA operon genes, respectively. Lipid profiles revealed reduced levels of PDIM in BCG-brain and BCG-lung and increased TAGs and Mycolic acid components in BCG-lung, compared to parent BCG-vaccine. In vitro infected cells showed that the BCG-lung induced a higher cytokine release, necrosis, and cell-associated bacterial load effect when compared to BCG-brain; conversely, both strains inhibited apoptosis and altered JAK-STAT signaling. Conclusions: During a chronic-disseminated BCG infection, BCG strains can evolve independently at different sites likely due to particular microenvironment features leading to differential antibiotic resistance, virulence traits resulting in dissimilar responses in different host tissues.

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BACKGROUND: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. METHODS: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20-75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. RESULT: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. CONCLUSION: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

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Bacterial, viral, and parasitic zoonotic diseases are transmitted to humans from a wide variety of animal species that act as reservoir hosts for the causative organisms. Zoonoses contribute an estimated 75% of new or reemerging infectious diseases in humans. All groups of mammals have been shown to act as hosts for transmission of different organisms that cause zoonoses, followed in importance by birds; with both wild and domestic species identified as hosts in specific cases. There has been considerable research progress leading to a better understanding of the host range, animal origin, evolution, and transmission of important zoonoses, including those caused by the ingestion of food and products derived from animals. Paleopathology studies of ancient human bone lesions, in combination with ancient DNA analysis of the causative pathogen, have contributed to our understanding of the origin of zoonotic diseases, including brucellosis and mycobacterial zoonoses. However, there are still knowledge gaps and new confirmed and potential hosts are reported locally with some frequency. Both the economic cost and burden of disease of zoonoses are substantial at local and global levels, as reflected by recent coronavirus pandemics that spread rapidly around the world. Evidence-based prevention strategies are currently a global priority increasingly recognized, especially in zoonoses-affected regions.

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Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.

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Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-ß1 (IL-12Rß1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.

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We present our experience in the hematopoietic stem cell transplantation (HSCT) in two children diagnosed with Mendelian susceptibility to mycobacterial diseases. The first child underwent a haploidentical HSCT with posttransplant cyclophosphamide using a reduced intensity conditioning following which he had primary graft failure. He was subsequently found to have interferon-γ1 receptor deficiency. He had immune reconstitution and is on antitubercular therapy. The second child diagnosed with IL12RB1 gene mutation underwent matched sibling donor HSCT with myeloablative conditioning following pretransplant immunosuppression with fludarabine and dexamethasone. He is 13 months post-HSCT with complete and remains disease free.

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BACKGROUND: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by increased susceptibility to weakly virulent mycobacteria (Bacillus Calmette-Guérin [BCG] vaccines and environmental mycobacteria), Mycobacterium tuberculosis, Candida spp. and Salmonella spp. The aim of this study is to evaluate clinical features and immunological findings of MSMD patients with interleukin 12 receptor beta 1 (IL12Rß1) deficiency. METHODS: Among 117 screened patients with BCG infection following vaccination, 23 suspected MSMD subjects were recruited to this study by the exclusion of severe combined immunodeficiencies and chronic granulomatous diseases. Flow cytometric assessment for surface expression of IL12Rß1 was performed. Moreover, the clinical and immunological data from the patients was evaluated. RESULTS: A significant decrease (less than 1%) in the surface expression of IL12Rß1 was reported in six cases which showed a significant increase in the count of lymphocytes (p=0.009) and CD8+ T cells (p=0.008) as compared to MSMD subjects with normal expression of surface IL12Rß1. The frequency of disseminated BCGosis (50% vs. 20%, p=0.29), recurrent infection (83.3% vs. 40%, p=0.14) and salmonellosis (33.3% vs. 0.0%, p=0.07) was higher in IL12Rß1 deficient subjects than IL12Rß1 sufficient individuals. CONCLUSION: MSMD patients with childhood onset of mycobacteriosis (mostly after BCG vaccination) and recurrent salmonellosis could be evaluated for IL12Rß1 expression with flow cytometry for punctual diagnosis.

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Few pathogens have shaped human medicine as the mycobacteria. From understanding biological phenomena driving disease spread, to mechanisms of host-pathogen interactions and antibiotic resistance, the Mycobacterium genus continues to challenge and offer insights into the basis of health and disease. Teleost fish models of mycobacterial infections have progressed significantly over the past three decades, now supplying a range of unique tools and new opportunities to define the strategies employed by these Gram-positive bacteria to overcome host defenses, as well as those host antimicrobial pathways that can be used to limit its growth and spread. Herein, we take a comparative perspective and provide an update on the contributions of teleost models to our understanding of mycobacterial diseases.

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Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare condition of primary immunodeficiency disorder. Interleukin-12 receptor ß1 (IL12RB1) deficiency, is the most common genetic etiology of MSMD, which is characterized by the selective predisposition to clinical disease caused by weakly-virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines, and environmental non-tuberculous mycobacteria (NTM). To the best of our knowledge, this is the first case of IL12RB1 deficiency to be reported from Iraq. Our case is an 8-year-old Syrian girl, for first-cousin parents, with a refugee-status in the North of Iraq. She had a history of disseminated BCG infection 2 months after receiving BCG vaccine, in addition to repeated episodes of mild or severe illnesses, such as maculopapular skin rash, lymphadenopathy, gastroenteritis, meningitis, and clinically diagnosed tuberculosis (TB) based on local TB-prevalence setting. Because of limited medical facilities in the war-torn countries; in Syria and Iraq, no diagnosis could be reached. We used Flinders Technology Associates (FTA) cards to transfer her bone marrow aspirate to Japan. A homozygous IL12RB1 mutation was detected by whole exome sequencing in Japan, using genomic-DNA extracted from dried bone marrow sample spots on FTA filter paper. In conclusion, diagnosis of MSMD due to IL12RB1 deficiency was possible by transferring the FTA sample of the patient for genetic evaluation in Japan. Our report recalls the need of pediatricians in countries with TB-prevalence and high parental consanguinity, to consider IL12RB1 deficiency in the differential diagnosis of a child with clinical evidence of TB, especially with the history of disseminated BCG disease.

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Mycobacteria cause a variety of diseases, such as tuberculosis, leprosy, and opportunistic diseases in immunocompromised people. The treatment of these diseases is problematic, necessitating the development of novel treatment strategies. Recently, ß-carbonic anhydrases (ß-CAs) have emerged as potential drug targets in mycobacteria. The genomes of mycobacteria encode for three ß-CAs that have been cloned and characterized from Mycobacterium tuberculosis (Mtb) and the crystal structures of two of the enzymes have been determined. Different classes of inhibitor molecules against Mtb ß-CAs have subsequently been designed and have been shown to inhibit these mycobacterial enzymes in vitro. The inhibition of these centrally important mycobacterial enzymes leads to reduced growth of mycobacteria, lower virulence, and impaired biofilm formation. Thus, the inhibition of ß-CAs could be a novel approach for developing drugs against the severe diseases caused by pathogenic mycobacteria. In the present article, we review the data related to in vitro and in vivo inhibition studies in the field.

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New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection with Mycobacterium tuberculosis We report here on our work with AX-35, an arylvinylpiperazine amide, and four related analogs, which are potent antitubercular agents in vitro All five compounds showed good activity against M. tuberculosisin vitro and in infected THP-1 macrophages, while displaying only mild cytotoxicity. Isolation and characterization of M. tuberculosis-resistant mutants to the arylvinylpiperazine amide derivative AX-35 revealed mutations in the qcrB gene encoding a subunit of cytochrome bc1 oxidase, one of two terminal oxidases of the electron transport chain. Cross-resistance studies, allelic exchange, transcriptomic analyses, and bioenergetic flux assays provided conclusive evidence that the cytochrome bc1-aa3 is the target of AX-35, although the compound appears to interact differently with the quinol binding pocket compared to previous QcrB inhibitors. The transcriptomic and bioenergetic profiles of M. tuberculosis treated with AX-35 were similar to those generated by other cytochrome bc1 oxidase inhibitors, including the compensatory role of the alternate terminal oxidase cytochrome bd in respiratory adaptation. In the absence of cytochrome bd oxidase, AX-35 was bactericidal against M. tuberculosis Finally, AX-35 and its analogs were active in an acute mouse model of TB infection, with two analogs displaying improved activity over the parent compound. Our findings will guide future lead optimization to produce a drug candidate for the treatment of TB and other mycobacterial diseases, including Buruli ulcer and leprosy.IMPORTANCE New drugs against Mycobacterium tuberculosis are urgently needed to deal with the current global TB pandemic. We report here on the discovery of a series of arylvinylpiperazine amides (AX-35 to AX-39) that represent a promising new family of compounds with potent in vitro and in vivo activities against M. tuberculosis AX compounds target the QcrB subunit of the cytochrome bc1 terminal oxidase with a different mode of interaction compared to those of known QcrB inhibitors. This study provides the first multifaceted validation of QcrB inhibition by recombineering-mediated allelic exchange, gene expression profiling, and bioenergetic flux studies. It also provides further evidence for the compensatory role of cytochrome bd oxidase upon QcrB inhibition. In the absence of cytochrome bd oxidase, AX compounds are bactericidal, an encouraging property for future antimycobacterial drug development.

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Nuclear factor (NF)-κB essential modifier (NEMO), also known as IκB kinase subunit-γ (IKKγ), is a pivotal molecule in the NF-κB signaling pathway. Mutations of NEMO cause incontinentia pigmenti and X-linked ectodermal dysplasia with immunodeficiency. Mendelian susceptibility to mycobacterial diseases (MSMD), which confers an almost selective predisposition to mycobacterial infection, is also caused by NEMO mutations. We herein report the first case of a patient with X-linked recessive (XR) MSMD who developed cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis. The relationship between NEMO mutation and oncogenesis is discussed.

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