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1.
J Infect Public Health ; 17(5): 780-788, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38518684

RESUMO

BACKGROUND: The genus Mycobacterium includes well-known bacteria such as M. tuberculosis causing tuberculosis and M. leprae causing leprosy. Additionally, various species collectively termed non-tuberculous mycobacteria (NTM) can cause infections in humans and animals, affecting individuals across all age groups and health conditions. However, information on NTM infection prevalence in Panama is limited. METHODS: This study conducted a retrospective analysis of clinical records from 2017 to 2021, specifically focusing on patients with NTM isolates. Data were categorized by variables like sex, age, HIV status, and sample source. RESULTS: Among the 4430 clinical records analyzed, 698 were linked to patients with NTM isolates. Of these patients, 397 were male, and 301 were female. Most female patients with NTM isolates (n = 190) were aged >45 to 85 years, while most male patients (n = 334) fell in the >25 to 75 years age group. A noteworthy proportion of male patients (n = 65) were aged 25-35 years. A significant age difference between male (median [min-max] = 53 years [3-90]) and female (median [61 years [6-94]) patients was observed (p < 0.001). Regarding HIV status, 77 positive individuals were male, and 19 were female (p < 0.001). Most samples (n = 566) were sputum samples, with additional pulmonary-associated samples such as broncho-alveolar lavage, tracheal secretions, and pleural fluid samples. Among extrapulmonary isolates (n = 48), sources included catheter secretions, intracellular fluids, peritoneal fluid, blood cultures, cerebrospinal fluid, bone marrow samples, and capillary transplant lesions. Specifically, the analysis identified the pathogenic microorganisms responsible for mycobacteriosis in Panama during the specific period 2017-2021, as M. fortuitum (34.4%), M. intracellulare (20.06%), and M. abscessus (13.75%), respectively. CONCLUSIONS: This study highlights the growing public health concern of NTM infections in Panama. The research provides valuable insights into the prevalence and distribution of NTM species in the country, offering a foundation for the development and implementation of effective prevention and control strategies for NTM infections in Panama.


Assuntos
Infecções por HIV , Infecções por Mycobacterium não Tuberculosas , Mycobacterium tuberculosis , Tuberculose , Animais , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Micobactérias não Tuberculosas , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Estudos Retrospectivos , Mycobacterium leprae , Panamá/epidemiologia , Tuberculose/complicações , Infecções por HIV/complicações
2.
Artigo em Chinês | MEDLINE | ID: mdl-38538244

RESUMO

Non-tuberculosis mycobacterium (NTM) refers to a general term for a large group of mycobacteria, excluding the mycobacterium tuberculosis and mycobacterium leprae, which is an opportunistic pathogen. NTM pulmonary disease and pulmonary tuberculosis have very similar clinical and imaging manifestations. Ordinary sputum tests can not distinguish between mycobacterium tuberculosis and NTM accurately, and it needs to be differentiated through detection methods such as mycobacterium culture medium, high-performance liquid chromatography, and molecular biology. During the diagnosis of occupational pneumoconiosis, a sandblasting and polishing worker's lung CT showed dynamic changes in infiltrating shadows and cavities in the right lung. A sputum drug sensitivity test showed NTM infection, but the patient refused treatment. After 20 months, the CT examination of the lung showed further enlargement of infiltrating shadows and cavities, and NTM bacterial identification showed intracellular mycobacterial infection. Amikacin, moxifloxacin, azithromycin, and ethambutol combined antibacterial treatment were given. Currently, the patient is still under treatment.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium tuberculosis , Silicose , Tuberculose Pulmonar , Humanos , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Tuberculose Pulmonar/complicações , Micobactérias não Tuberculosas , Silicose/complicações
3.
Chem Biodivers ; 21(5): e202400067, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38500408

RESUMO

Tuberculosis is a communicable disease which affects humans particularly the lungs and is transmitted mainly through air. Despite two decades of intensive research aimed at understanding and combating tuberculosis, persistent biological uncertainties continue to hinder progress. Nowadays, heterocyclic compounds have proven themselves in effective treatment of tuberculosis because of their wide range of biological and pharmacological activities. Antituberculosis or antimycobacterial agents encompass a broad array of compounds utilized singly or in conjunction to combat Mycobacterium infections, spanning from tuberculosis to leprosy. Here, we summarize the synthesis of various heterocyclic compounds which includes the greener synthetic route as well as use of nano compounds as catalyst along with their anti TB activities.


Assuntos
Antituberculosos , Compostos Heterocíclicos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese química , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Estrutura Molecular
4.
Microb Pathog ; 188: 106557, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38272330

RESUMO

The Notch signaling pathway is the most crucial link in the normal operation and maintenance of physiological functions of mammalian life processes. Notch receptors interact with ligands and this leads to three cleavages and goes on to enter the nucleus to initiate the transcription of target genes. The Notch signaling pathway deeply participates in the differentiation and function of various cells, including immune cells. Recent studies indicate that the outcomes of Notch signaling are changeable and highly dependent on different bacterial infection. The Notch signaling pathway plays a different role in promoting and inhibiting bacterial infection. In this review, we focus on the latest research findings of the Notch signaling pathway in bacterial infectious diseases. The Notch signaling pathway is critically involved in a variety of development processes of immunosuppression of different APCs. The Notch signaling pathway leads to functional changes in epithelial cells to aggravate tissue damage. Specifically, we illustrate the regulatory mechanism of the Notch signaling pathway in various bacterial infections, such as Mycobacterium tuberculosis, Mycobacterium avium paratuberculosis, Mycobacterium leprae, Helicobacter pylori, Klebsiella pneumoniae, Bacillus subtilis, Staphylococcus aureus, Ehrlichia chaffeensis and sepsis. Collectively, this review will not only help beginners intuitively and systematically understand the Notch signaling pathway in bacterial infectious diseases but also help experts to generate fresh insight in this field.


Assuntos
Infecções Bacterianas , Doenças Transmissíveis , Mycobacterium tuberculosis , Animais , Humanos , Transdução de Sinais , Receptores Notch/metabolismo , Mycobacterium tuberculosis/metabolismo , Mamíferos/metabolismo
5.
Biochimie ; 216: 46-55, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37879428

RESUMO

Mycobacteria are microorganisms distributed in the environment worldwide, and some of them, such as Mycobacterium tuberculosis or M. leprae, are pathogenic. The hydrophobic mycobacterial cell envelope has low permeation and bacteria need to export products across their structure. Mycobacteria possess specialized protein secretion systems, such as the Early Secretory Antigenic Target 6 secretion (ESX) system. Five ESX loci have been described in M. tuberculosis, called ESX-1 to ESX-5. The ESX-3 secretion system has been associated with mycobacterial metabolism and growth. The locus of this system is highly conserved across mycobacterial species. Metallo-proteins regulate negative ESX-3 transcription in high conditions of iron and zinc. Moreover, this secretion system is part of an antioxidant regulatory pathway linked to Zinc. EccA3, EccB3, EccC3, EccD3, and EccE3 are components of the ESX-3 secretion machinery, whereas EsxG-EsxH, PE5-PPE4, and PE15-PPE20 are proteins secreted by this system. In addition, EspG3 and MycP3 are complementary proteins involved in transport and proteolysis respectively. This system is associated to mycobacterial virulence by releasing the bacteria from the phagosome and inhibiting endomembrane damage response. Furthermore, components of this system inhibit the host immune response by reducing the recognition of M. tuberculosis-infected cells. The components of the ESX-3 secretion system play a role in drug resistance and cell wall integrity. Moreover, the expression data of this system indicated that external and internal factors affect ESX-3 locus expression. This review provides an overview of new findings on the ESX-3 secretion system, its regulation, expression, and functions.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Sistemas de Secreção Tipo VII , Humanos , Sistemas de Secreção Tipo VII/genética , Sistemas de Secreção Tipo VII/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mycobacterium tuberculosis/metabolismo , Zinco/metabolismo
6.
Int J Mycobacteriol ; 12(4): 513-515, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38149553

RESUMO

A 35-year-old male patient with lepromatous leprosy came to the emergency room (ER) due to breathlessness and chest pain. The patient was diagnosed with pulmonary tuberculosis (TB) after a bronchoscopy and started on antitubercular therapy. However, the patient continued to experience tachycardia and desaturation, and on further evaluation, Computed tomography pulmonary angiography revealed an embolus in the right descending pulmonary artery. The patient was found to have an elevated d-dimer. Further investigation revealed that the cause of the pulmonary thromboembolism (PTE) was the thalidomide medication that the patient was taking for type 2 leprosy reaction. The medication was stopped, and the patient was treated with low-molecular-weight heparin and discharged with apixaban for six months. The patient's condition improved on follow-up. This case is unique due to the rare combination of pulmonary TB, leprosy, and pulmonary embolism brought on by thalidomide administration. Physicians should be aware of the possibility of co-infection of TB and leprosy and the need to rule out thromboembolism when patients are on thalidomide.


Assuntos
Coinfecção , Hanseníase , Mycobacterium tuberculosis , Embolia Pulmonar , Tuberculose Pulmonar , Masculino , Humanos , Adulto , Mycobacterium leprae , Talidomida/uso terapêutico , Coinfecção/diagnóstico , Hanseníase/complicações , Hanseníase/diagnóstico , Hanseníase/tratamento farmacológico , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico
7.
Arch Microbiol ; 206(1): 46, 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38153595

RESUMO

We examined literature on Mycobacterium tuberculosis (Mtb) subsequent to its genome release, spanning years 1999-2020. We employed scientometric mapping, entity mining, visualization techniques, and PubMed and PubTator databases. Most popular keywords, most active research groups, and growth in quantity of publications were determined. By gathering annotations from the PubTator, we determined direction of research in the areas of drug hypersensitivity, drug resistance (AMR), and drug-related side effects. Additionally, we examined the patterns in research on Mtb metabolism and various forms of tuberculosis, including skin, brain, pulmonary, extrapulmonary, and latent tuberculosis. We discovered that 2011 had the highest annual growth rate of publications, at 19.94%. The USA leads the world in publications with 18,038, followed by China with 14,441, and India with 12,158 publications. Studies on isoniazid and rifampicin resistance showed an enormous increase. Non-tuberculous mycobacteria also been the subject of more research in effort to better understand Mtb physiology and as model organisms. Researchers also looked at co-infections like leprosy, hepatitis, plasmodium, HIV, and other opportunistic infections. Host perspectives like immune response, hypoxia, and reactive oxygen species, as well as comorbidities like arthritis, cancer, diabetes, and kidney disease etc. were also looked at. Symptomatic aspects like fever, coughing, and weight loss were also investigated. Vitamin D has gained popularity as a supplement during illness recovery, however, the interest of researchers declined off late. We delineated dominant researchers, journals, institutions, and leading nations globally, which is crucial for aligning ongoing and evolving landscape of TB research efforts. Recognising the dominant patterns offers important information about the areas of focus for current research, allowing biomedical scientists, clinicians, and organizations to strategically coordinate their efforts with the changing priorities in the field of tuberculosis research.


Assuntos
Mycobacterium tuberculosis , Infecções Oportunistas , Tuberculose , Humanos , Tuberculose/tratamento farmacológico , Isoniazida , Mycobacterium tuberculosis/genética , Descoberta de Drogas
8.
Nat Commun ; 14(1): 5803, 2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37726269

RESUMO

The cell walls of pathogenic and acidophilic bacteria, such as Mycobacterium tuberculosis and Mycobacterium leprae, contain lipoarabinomannan and arabinogalactan. These components are composed of D-arabinose, the enantiomer of the typical L-arabinose found in plants. The unique glycan structures of mycobacteria contribute to their ability to evade mammalian immune responses. In this study, we identified four enzymes (two GH183 endo-D-arabinanases, GH172 exo-α-D-arabinofuranosidase, and GH116 exo-ß-D-arabinofuranosidase) from Microbacterium arabinogalactanolyticum. These enzymes completely degraded the complex D-arabinan core structure of lipoarabinomannan and arabinogalactan in a concerted manner. Furthermore, through biochemical characterization using synthetic substrates and X-ray crystallography, we elucidated the mechanisms of substrate recognition and anomer-retaining hydrolysis for the α- and ß-D-arabinofuranosidic bonds in both endo- and exo-mode reactions. The discovery of these D-arabinan-degrading enzymes, along with the understanding of their structural basis for substrate specificity, provides valuable resources for investigating the intricate glycan architecture of mycobacterial cell wall polysaccharides and their contribution to pathogenicity.


Assuntos
Endometriose , Mycobacterium tuberculosis , Animais , Feminino , Humanos , Galactanos , Lipopolissacarídeos , Mamíferos
9.
Tuberculosis (Edinb) ; 142: 102393, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37684080

RESUMO

In recent years, our knowledge of leprosy in the past has substantially been enriched. Nonetheless, much still remains to be discovered, especially in regions and periods from where no written sources are available. To fill in some research gaps, we provide the comparative analysis of eight Avar-period leprosy cases from the Danube-Tisza Interfluve (Hungary). In every case, to reconstruct the biological consequences of leprosy, the detected bony changes were linked with palaeopathological and modern medical information. To reconstruct the social consequences of being affected by leprosy, conceptualisation of the examined individuals' treatment in death was conducted. In every case, the disease resulted in deformation and disfigurement of the involved anatomical areas (rhinomaxillary region, feet, and/or hands) with difficulties in conducting certain physical activities. These would have been disadvantageous for the examined individuals and limited or changed their possibilities to participate in social situations. The most severe cases would have required continuous support from others to survive. Our findings indicate that, despite their very visible disease and associated debility, the examined communities did not segregate leprosy sufferers but provided and cared for them, and maintained a strong enough social network that made their survival possible even after becoming incapable of self-sufficiency.


Assuntos
Hanseníase , Mycobacterium tuberculosis , Humanos , Hungria , Lacunas de Evidências , Hanseníase/diagnóstico , Hanseníase/tratamento farmacológico , Sulfacetamida
10.
Tuberculosis (Edinb) ; 142: 102377, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37531864

RESUMO

The Many Hosts of Mycobacteria (MHM) meeting series brings together basic scientists, clinicians and veterinarians to promote robust discussion and dissemination of recent advances in our knowledge of numerous mycobacterial diseases, including human and bovine tuberculosis (TB), nontuberculous mycobacteria (NTM) infection, Hansen's disease (leprosy), Buruli ulcer and Johne's disease. The 9th MHM conference (MHM9) was held in July 2022 at The Ohio State University (OSU) and centered around the theme of "Confounders of Mycobacterial Disease." Confounders can and often do drive the transmission of mycobacterial diseases, as well as impact surveillance and treatment outcomes. Various confounders were presented and discussed at MHM9 including those that originate from the host (comorbidities and coinfections) as well as those arising from the environment (e.g., zoonotic exposures), economic inequality (e.g. healthcare disparities), stigma (a confounder of leprosy and TB for millennia), and historical neglect (a confounder in Native American Nations). This conference report summarizes select talks given at MHM9 highlighting recent research advances, as well as talks regarding the historic and ongoing impact of TB and other infectious diseases on Native American Nations, including those in Southwestern Alaska where the regional TB incidence rate is among the highest in the Western hemisphere.


Assuntos
Coinfecção , Infecções por Mycobacterium não Tuberculosas , Mycobacterium tuberculosis , Tuberculose Bovina , Animais , Bovinos , Humanos , Micobactérias não Tuberculosas , Infecções por Mycobacterium não Tuberculosas/microbiologia
11.
ACS Chem Biol ; 18(7): 1548-1556, 2023 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-37306676

RESUMO

Mycobacteria and other organisms in the order Mycobacteriales cause a range of significant human diseases, including tuberculosis, leprosy, diphtheria, Buruli ulcer, and non-tuberculous mycobacterial (NTM) disease. However, the intrinsic drug tolerance engendered by the mycobacterial cell envelope undermines conventional antibiotic treatment and contributes to acquired drug resistance. Motivated by the need to augment antibiotics with novel therapeutic approaches, we developed a strategy to specifically decorate mycobacterial cell surface glycans with antibody-recruiting molecules (ARMs), which flag bacteria for binding to human-endogenous antibodies that enhance macrophage effector functions. Mycobacterium-specific ARMs consisting of a trehalose targeting moiety and a dinitrophenyl hapten (Tre-DNPs) were synthesized and shown to specifically incorporate into outer-membrane glycolipids of Mycobacterium smegmatis via trehalose metabolism, enabling recruitment of anti-DNP antibodies to the mycobacterial cell surface. Phagocytosis of Tre-DNP-modified M. smegmatis by macrophages was significantly enhanced in the presence of anti-DNP antibodies, demonstrating proof-of-concept that our strategy can augment the host immune response. Because the metabolic pathways responsible for cell surface incorporation of Tre-DNPs are conserved in all Mycobacteriales organisms but absent from other bacteria and humans, the reported tools may be enlisted to interrogate host-pathogen interactions and develop immune-targeting strategies for diverse mycobacterial pathogens.


Assuntos
Mycobacterium tuberculosis , Mycobacterium , Tuberculose , Humanos , Trealose , Mycobacterium smegmatis , Membrana Celular , Mycobacterium tuberculosis/química
12.
EBioMedicine ; 93: 104649, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37327675

RESUMO

BACKGROUND: Expansion of antimicrobial resistance monitoring and epidemiological surveillance are key components of the WHO strategy towards zero leprosy. The inability to grow Mycobacterium leprae in vitro precludes routine phenotypic drug susceptibility testing, and only limited molecular tests are available. We evaluated a culture-free targeted deep sequencing assay, for mycobacterial identification, genotyping based on 18 canonical SNPs and 11 core variable-number tandem-repeat (VNTR) markers, and detection of rifampicin, dapsone and fluoroquinolone resistance-associated mutations in rpoB/ctpC/ctpI, folP1, gyrA/gyrB, respectively, and hypermutation-associated mutations in nth. METHODS: The limit of detection (LOD) was determined using DNA of M. leprae reference strains and from 246 skin biopsies and 74 slit skin smears of leprosy patients, with genome copies quantified by RLEP qPCR. Sequencing results were evaluated versus whole genome sequencing (WGS) data of 14 strains, and versus VNTR-fragment length analysis (FLA) results of 89 clinical specimens. FINDINGS: The LOD for sequencing success ranged between 80 and 3000 genome copies, depending on the sample type. The LOD for minority variants was 10%. All SNPs detected in targets by WGS were identified except in a clinical sample where WGS revealed two dapsone resistance-conferring mutations instead of one by Deeplex Myc-Lep, due to partial duplication of the sulfamide-binding domain in folP1. SNPs detected uniquely by Deeplex Myc-Lep were missed by WGS due to insufficient coverage. Concordance with VNTR-FLA results was 99.4% (926/932 alleles). INTERPRETATION: Deeplex Myc-Lep may help improve the diagnosis and surveillance of leprosy. Gene domain duplication is an original putative drug resistance-related genetic adaptation in M. leprae. FUNDING: EDCTP2 programme supported by the European Union (grant number RIA2017NIM-1847 -PEOPLE). EDCTP, R2Stop: Effect:Hope, The Mission To End Leprosy, the Flemish Fonds Wetenschappelijk Onderzoek.


Assuntos
Hanseníase , Mycobacterium tuberculosis , Humanos , Mycobacterium leprae/genética , Testes de Sensibilidade Microbiana , Genótipo , Farmacorresistência Bacteriana/genética , Hanseníase/diagnóstico , Hanseníase/tratamento farmacológico , Hanseníase/epidemiologia , Dapsona , Biópsia , Resistência a Múltiplos Medicamentos
13.
Tuberculosis (Edinb) ; 140: 102345, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37116235

RESUMO

CD11b+Gr-1low cells that are increased in the lungs of a Mycobacterium (M) tuberculosis-infection mouse model have the characteristics of monocytic (M)-myeloid-derived suppressor cells (MDSCs) and harbor M.tuberculosis. Interestingly, a high number of M-MDSCs have also been observed in skin lesions of patients with lepromatous leprosy. We hypothesized that CD11b+Gr-1low cells might be involved in the pathogenesis of leprosy, as they are in tuberculosis. In the current study, we investigated the issue of whether CD11b+Gr-1low cells accumulate in Mycobacterium (M) leprae-induced granulomas of the footpad skin of nude mice. Our results show that CD11b+Gr-1low cells began to accumulate in the 7-month-old M.leprae-induced granulomas and were replaced by other leukocytes, including CD11b+Gr-1high over time during M.leprae infections. CD11b + Gr-1low cells expressed the surface markers of M-MDSC, Ly6Chigh and Ly6Glow. In addition, CD11b+Gr-1low cells have the nuclei of a mononuclear cell type and expressed higher levels of arginase 1 (Arg1) and inducible NO synthetase (iNOS). Furthermore, they showed a higher infection rate by M.leprae. Taken together, our results indicate that the inoculation with M.leprae induced an accumulation of CD11b + Gr-1low at a relatively early stage, 7-month-old M.leprae-induced granulomas, and that CD11b+Gr-1low have the characteristics of M-MDSC and may act as a reservoir for M.leprae.


Assuntos
Mycobacterium tuberculosis , Células Supressoras Mieloides , Tuberculose , Camundongos , Animais , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Camundongos Nus , Mycobacterium tuberculosis/metabolismo , Tuberculose/metabolismo , Granuloma/induzido quimicamente , Granuloma/metabolismo , Antígeno CD11b/metabolismo
14.
Dis Model Mech ; 16(3)2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36951140

RESUMO

Professor Lalita Ramakrishnan is at the forefront of modern tuberculosis (TB) research. She has developed vital tools, most notably a robust zebrafish model, to study this disease, leading to seminal discoveries uncovering bacterial and host interactions throughout infection. Her group has harnessed this knowledge to develop new treatments for TB and shape clinical research. By unveiling these complex interactions, they have also improved our understanding of fundamental biology of macrophages and other infectious diseases, such as leprosy.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Feminino , Peixe-Zebra , Tuberculose/microbiologia , Macrófagos , Interações Hospedeiro-Patógeno
15.
Microb Drug Resist ; 29(5): 190-212, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36809064

RESUMO

Mycobacteria species include a large number of pathogenic organisms such as Mycobacterium tuberculosis, Mycobacterium leprae, and various non-tuberculous mycobacteria. Mycobacterial membrane protein large 3 (MmpL3) is an essential mycolic acid and lipid transporter required for growth and cell viability. In the last decade, numerous studies have characterized MmpL3 with respect to protein function, localization, regulation, and substrate/inhibitor interactions. This review summarizes new findings in the field and seeks to assess future areas of research in our rapidly expanding understanding of MmpL3 as a drug target. An atlas of known MmpL3 mutations that provide resistance to inhibitors is presented, which maps amino acid substitutions to specific structural domains of MmpL3. In addition, chemical features of distinct classes of Mmpl3 inhibitors are compared to provide insights into shared and unique features of varied MmpL3 inhibitors.


Assuntos
Proteínas de Membrana , Mycobacterium tuberculosis , Proteínas de Membrana/metabolismo , Proteínas de Bactérias/metabolismo , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Mycobacterium tuberculosis/genética , Antituberculosos/farmacologia
16.
J Bacteriol ; 205(1): e0033722, 2023 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-36598232

RESUMO

The genus Mycobacterium contains several slow-growing human pathogens, including Mycobacterium tuberculosis, Mycobacterium leprae, and Mycobacterium avium. Mycobacterium smegmatis is a nonpathogenic and fast growing species within this genus. In 1990, a mutant of M. smegmatis, designated mc2155, that could be transformed with episomal plasmids was isolated, elevating M. smegmatis to model status as the ideal surrogate for mycobacterial research. Classical bacterial models, such as Escherichia coli, were inadequate for mycobacteria research because they have low genetic conservation, different physiology, and lack the novel envelope structure that distinguishes the Mycobacterium genus. By contrast, M. smegmatis encodes thousands of conserved mycobacterial gene orthologs and has the same cell architecture and physiology. Dissection and characterization of conserved genes, structures, and processes in genetically tractable M. smegmatis mc2155 have since provided previously unattainable insights on these same features in its slow-growing relatives. Notably, tuberculosis (TB) drugs, including the first-line drugs isoniazid and ethambutol, are active against M. smegmatis, but not against E. coli, allowing the identification of their physiological targets. Furthermore, Bedaquiline, the first new TB drug in 40 years, was discovered through an M. smegmatis screen. M. smegmatis has become a model bacterium, not only for M. tuberculosis, but for all other Mycobacterium species and related genera. With a repertoire of bioinformatic and physical resources, including the recently established Mycobacterial Systems Resource, M. smegmatis will continue to accelerate mycobacterial research and advance the field of microbiology.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Humanos , Mycobacterium smegmatis/genética , Escherichia coli/genética , Mycobacterium tuberculosis/genética , Isoniazida
17.
Microbiol Spectr ; 11(1): e0432622, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36622171

RESUMO

Mycobacterium avium complex (MAC) thrives in various environments and mainly causes lung disease in humans. Because macrolide antibiotics such as clarithromycin or azithromycin are key drugs for MAC lung disease, the emergence of macrolide-resistant strains prevents the treatment of MAC. More than 95% of macrolide-resistant MAC strains are reported to have a point mutation in 23S rRNA domain V. This study successfully developed a melting curve assay using nonfluorescent labeled probes to detect the MAC mutation at positions 2058 to 2059 of the 23S rRNA gene (AA genotype, clarithromycin susceptible; TA, GA, AG, CA, AC, and AT genotypes, clarithromycin resistant). In the AA-specific probe assay, the melting peak of the DNA fragment of the AA genotype was higher than that of DNA fragments of other genotypes. Melting temperature (Tm) values of the AA genotype and the other genotypes were about 80°C and 77°C, respectively. DNA fragments of each genotype were identified correctly in six other genotype-specific probes (TA, GA, AG, CA, AC, and AT) assays. Using genomic DNA from six genotype strains of M. avium and four genotype strains of M. intracellulare, we confirmed that all genomic DNAs could be correctly identified as individual genotypes according to the highest Tm values among the same probe assays. These results indicate that this melting curve-based assay is able to determine MAC genotypes at positions 2058 to 2059 of the 23S rRNA gene. This simple method could contribute to the rapid detection of clarithromycin-resistant MAC strains and help to provide accurate drug therapy for MAC lung disease. IMPORTANCE Since macrolide antibiotics such as clarithromycin or azithromycin are key drugs in multidrug therapy for Mycobacterium avium complex (MAC) lung diseases, the rapid detection of macrolide-resistant MAC strains has important implications for the treatment of MAC. Previous studies have reported a correlation between drug susceptibility testing and the mutation of macrolide resistance genes. In this study, we developed a novel melting curve-based assay using nonfluorescent labeled probes to identify both clarithromycin-resistant M. avium and M. intracellulare with mutations in the 23S rRNA gene, which is the clarithromycin or azithromycin resistance gene. This assay contributed to not only the detection of MAC mutations but also the determination of all genotypes at positions 2058 to 2059 of the 23S rRNA gene. Furthermore, because nonfluorescent labeled probes are used, this assay is more easily and more immediately available than other methods.


Assuntos
Pneumopatias , Infecção por Mycobacterium avium-intracellulare , Mycobacterium tuberculosis , Humanos , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Complexo Mycobacterium avium/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Macrolídeos/uso terapêutico , Testes de Sensibilidade Microbiana , Quimioterapia Combinada , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Farmacorresistência Bacteriana/genética , Hansenostáticos/uso terapêutico , Pneumopatias/tratamento farmacológico
18.
Front Cell Infect Microbiol ; 12: 997283, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325467

RESUMO

Tuberculosis (TB) is among the most difficult infections to treat, requiring several months of multidrug therapy to produce a durable cure. The reasons necessitating long treatment times are complex and multifactorial. However, one major difficulty of treating TB is the resistance of the infecting bacterium, Mycobacterium tuberculosis (Mtb), to many distinct classes of antimicrobials. This review will focus on the major gaps in our understanding of intrinsic drug resistance in Mtb and how functional and chemical-genetics can help close those gaps. A better understanding of intrinsic drug resistance will help lay the foundation for strategies to disarm and circumvent these mechanisms to develop more potent antitubercular therapies.


Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Humanos , Mycobacterium tuberculosis/genética , Quimioterapia Combinada , Hansenostáticos/uso terapêutico , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Resistência a Medicamentos
19.
Curr Microbiol ; 79(11): 345, 2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209340

RESUMO

Tuberculosis (TB) is a major zoonotic disease of public health importance worldwide. Its burden is more in developing countries due to inadequate surveillance, co-infection with HIV/AIDS and poor social amenities; hence consumption of unpasteurized milk, contaminated meat and inhalation of infected droplets from animals or patients with active TB are the major risk practices. A survey was conducted on TB prevalence from 2013 to 2014 while patients records from TB and Leprosy units of hospitals in the three Agricultural zones (Ogoja, Ikom and Calabar) of Cross River State, Nigeria were assessed from 2000 to 2010. Out of 1,170 sampled patients, 8 (0.7%) were positive, of which 6 and 2 isolates were identified as M. tuberculosis and M. bovis, respectively. Out of 52,558 studied patients files, 235 (0.4%) were positive with varied annual prevalence; the highest (1.0%) and lowest (0.2%) in 2009 and 2011, respectively. The prevalence was higher in dry (0.9% and 0.5%) than the rainy season (0.5% and 0.4%), in females (0.9% and 0.5%) than the males (0.4% and 0.4%) in the survey and retrospective studies, respectively. The age distribution of TB among the patients were; (0% and 0.3%), (0.4% and 0.4%), (0.7% and 0.4%) and (1.5% and 0.7%) for those (≤ 18), (19-40), (41-60) and (> 60) yrs old in the survey and retrospective study, respectively. TB is prevalent in human patients in Cross River State hence, the need for sustainable campaign, continuous surveillance and private/ public health partnership in accurate and early diagnosis, treatment and one health approach to its control.


Assuntos
Infecções por HIV , Mycobacterium tuberculosis , Saúde Única , Tuberculose , Animais , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Nigéria/epidemiologia , Prevalência , Estudos Retrospectivos , Tuberculose/epidemiologia
20.
Subcell Biochem ; 99: 379-391, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36151383

RESUMO

The mycobacteria genus is responsible for numerous infectious diseases that have afflicted the human race since antiquity-tuberculosis and leprosy in particular. An important contributor to their evolutionary success is their unique cell envelope, which constitutes a quasi-impermeable barrier, protecting the microorganism from external threats, antibiotics included. The arabinofuranosyltransferases are a family of enzymes, unique to the Actinobacteria family that mycobacteria genus belongs to, that are critical to building of this cell envelope. In this chapter, we will analyze available structures of members of the mycobacterial arabinofuranosyltransferase, clarify their function, as well as explore the common themes present amongst this family of enzymes, as revealed by recent research.


Assuntos
Mycobacterium tuberculosis , Mycobacterium , Antibacterianos , Membrana Celular , Parede Celular , Humanos
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