- Incidence and Predictors of Tuberculosis among HIV-positive Children in Adama Referral Hospital and Medical College, East Shoa Ethiopia: A retrospective follow up study. [Journal Article]
- EHEpidemiol Health 2019 Jun 22; :e2019028
- CONCLUSIONS: Incidence of TB was high, particularly in the pre-ART groups receiving HIV chronic care. Close follow up of HIV positive children is crucial to safeguard them against the development of TB.IPT, averting malnutrition and anemia has also significant importance.
- Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location. [Journal Article]
- FRFree Radic Biol Med 2019 Jul 15
- Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl radical, which was considered to be r…
Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl radical, which was considered to be responsible for its anti-tuberculosis activity. However, it is still not clear whether the previously-proposed N-centered isoniazidyl radical intermediate can be initially produced or not; and if so, what is its exact location on the hydrazine group, distal- or proximal-nitrogen? Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the characteristic and transient N-centered isoniazidyl radical intermediate can be detected and identified from INH activation uniquely by Mn(III)Acetate not by Mn(III) pyrophosphate. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by 15N-isotope-labeling techniques via using 15N-labeled INH. Diisonicotinyl hydrazine was identified as a new reaction product from INH/Mn(III). Analogous results were observed with other hydrazides. This study represents the first detection and unequivocal identification of the initial N-centered isoniazidyl radical and its exact location. These findings should provide a new perspective on the molecular mechanism of INH activation, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.
- Management of patients with multidrug-resistant tuberculosis. [Journal Article]
- IJInt J Tuberc Lung Dis 2019 Jun 01; 23(6):645-662
- The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before i…
The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.
- Identification and Characterization of Genetic Determinants of Isoniazid and Rifampicin Resistance in Mycobacterium tuberculosis in Southern India. [Journal Article]
- SRSci Rep 2019 Jul 16; 9(1):10283
- Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to unders…
Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface.
- [Osseous Tuberculosis - interdisciplinary treatment from diagnostics to microsurgical defect reconstruction - Case report and review of the literature and proposal of a therapeutic algorithm]. [Journal Article]
- HMHandchir Mikrochir Plast Chir 2019 Jul 16
- Tuberculosis is a central global health problem with an incidence of 10 million new cases per year and more than one million deaths per year. Contrary to this, osseous tuberculosis represents an extr…
Tuberculosis is a central global health problem with an incidence of 10 million new cases per year and more than one million deaths per year. Contrary to this, osseous tuberculosis represents an extremely rare entity of tuberculosis. Osseous tuberculosis is challenging beginning with the correct diagnosis, adequate surgical as well infectiological treatment as well as extremity reconstruction. Facing increased migration and therefore increasing numbers of cases of tuberculosis in western countries, the question of a reliable diagnosis, therapy and protective measures in dealing with those patients is becoming increasingly important for Central Europe.In the present case, a 49-year-old female patient from Pakistan, the first presented to our institution with a clinical picture of an exanthema at the level of the upper ankle joint with radiological signs of osteolysis. Pathological and molecular pathological diagnostics revealed the presence of an infection caused by Mycobacteria tuberculosis complex. In the initial phase over 6 weeks, a 4-fold therapy with isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) and ethambutol (EMB) was administered in accordance with the WHO guidelines, followed by 2-fold therapy with INH and RMP for 12 months in the subsequent continuity phase.14 months later, the patient was re-admitted to hospital because of a recurrent abscess. Therefore tuberculostatic therapy as a quadruple combination of INH, RMP, PZA and EMB was initiated for 6 weeks and as a double combination of INH and RMP for a total of one year.After the abscess had been eradicated, the joint was immobilized by ankle arthrodesis and the deep necrosis of the right ankle was finally reconstructed with allergenic bone grafts and a free microvascular M. gracilis flap.In the case presented here, successful treatment was possible via an interdisciplinary treatment consisiting of infectiology, orthopaedic surgery as well as plastic surgery specialists. Osseous tuberculosis could be eradicated and the bony defect could be reconstructed together with resulting soft tissue defect ultimately preserving of the extremity. In the context of this case study, a comprehensive overview of the current literature is described and a therapy algorithm is proposed due to the increasing relevance of this entity.
- Molecular characterization and antimicrobial resistance profiles of Mycobacterium tuberculosis complex in environmental substrates from three dairy farms in Eastern Cape, South Africa. [Journal Article]
- IJInt J Environ Health Res 2019 Jul 15; :1-10
- This study analysed 330 environmental substrates from three dairy farms for the occurrence, drug resistance and the genetic mutations of MTBC (Mycobacterium tuberculosis complex) in Eastern Cape, Sou…
This study analysed 330 environmental substrates from three dairy farms for the occurrence, drug resistance and the genetic mutations of MTBC (Mycobacterium tuberculosis complex) in Eastern Cape, South Africa using PCR, while the Genotype MTBDRplus assay was used for drug susceptibility and genetic mutations analyses. About 17% (55/330) of the samples were positive for MTBC at 16.7% (water), 13.3% (soil) and 20% (hayfeed). Isoniazid resistance was detected in 47.3% (26/55) of the samples while 16.4% (9/55) were multidrug-resistant. Genetic mutations were detected on the rpoB gene (resistance to rifampicin) with frequencies ranging from 53.6% (D516V) to 21.4% (H526D), while mutations on the katG and inhA genes (resistance to isoniazid) ranged between 14.3% and 80%. Incidents of diverse genetic mutations in the environmental matrices suggest possible resistance to other anti-TB drugs not assayed in this study and emphasizes the need for continuous monitoring of drug resistance patterns for timely detection and control of new clonal groups of MTBC.
- Evaluation of in silico designed inhibitors targeting MelF (Rv1936) against Mycobacterium marinum within macrophages. [Journal Article]
- SRSci Rep 2019 Jul 12; 9(1):10084
- We recently identified inhibitors targeting Mycobacterium marinum MelF (Rv1936) by in silico analysis, which exhibited bacteriostatic/bactericidal activity against M. marinum and M. tuberculosis in v…
We recently identified inhibitors targeting Mycobacterium marinum MelF (Rv1936) by in silico analysis, which exhibited bacteriostatic/bactericidal activity against M. marinum and M. tuberculosis in vitro. Herein, we evaluated the effect of best four inhibitors (# 5175552, # 6513745, # 5255829, # 9125618) obtained from the ChemBridge compound libraries, on intracellular replication and persistence of bacteria within IFN-γ activated murine RAW264.7 and human THP-1 macrophages infected with M. marinum. Inhibitors # 5175552 and # 6513745 significantly reduced (p < 0.05) the intracellular replication of bacilli during day 7 post-infection (p.i.) within RAW264.7 and THP-1 macrophages infected at multiplicity of infection (MOI) of ~1.0. These observations were substantiated by electron microscopy, which revealed the protective effect of # 5175552 in clearing the bacilli inside murine macrophages. Strikingly, # 6513745 displayed synergism with isoniazid against M. marinum in murine macrophages, whereas # 5175552 significantly suppressed (p < 0.05) the persistent bacilli during day 10-14 p.i. in infected RAW264.7 and THP-1 macrophages (MOI of ~ 0.1). Moreover, # 5175552 and # 6513745 were non-cytotoxic to host macrophages at both 1X and 5X MIC. Further validation of these inhibitors against M. tuberculosis-infected macrophages and animal models has potential for development as novel anti-tubercular agents.
- Use of nanotechnology for infectious disease diagnostics: application in drug resistant tuberculosis. [Journal Article]
- BIBMC Infect Dis 2019 Jul 12; 19(1):618
- CONCLUSIONS: The AuNP based lateral flow assay was capable of differentiating the specific mutation and the wild type along with MTb identification within 3 h.
- Insight into genetic diversity of Mycobacterium tuberculosis in Kandy, Sri Lanka reveals predominance of the Euro-American lineage. [Journal Article]
- IJInt J Infect Dis 2019 Jul 09
- CONCLUSIONS: The population structure of MTB in Kandy, Sri Lanka was different from the South Asian Region. Clonal expansion of locally evolved lineage 4/SIT3234 and detection of the pre-MDR Beijing isolates from new TB patients is alarming and will require continuous monitoring.
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- DFT study on the effect of proximal residues on the Mycobacterium tuberculosis catalase-peroxidase (katG) heme compound I intermediate and its bonding interaction with isoniazid. [Journal Article]
- PCPhys Chem Chem Phys 2019 Jul 12
- Isoniazid (INH) is converted into isonicotinyl radical through its interaction with the catalase-peroxidase (katG) enzyme present in the cells of Mycobacterium tuberculosis (M. tb.), the bacteria tha…
Isoniazid (INH) is converted into isonicotinyl radical through its interaction with the catalase-peroxidase (katG) enzyme present in the cells of Mycobacterium tuberculosis (M. tb.), the bacteria that causes the tuberculosis disease. This process is important because resistance of M. tb. cells to INH treatment has been associated with the failure of completion of this process. However, this process is poorly understood and there are a variety of conflicting theories about the details of the mechanism of this process. One theory suggests that INH binds to katG and transfers a single electron to the heme while the heme is in its two electron oxidized state, compound I [Fe(iv)Por˙+] (CpdI). In this study, DFT calculations at the UB3LYP/6-31g(d)-LANL2DZ level of theory are used to study the M. tb. katG CpdI molecule. Different models of the M. tb. CpdI molecule were prepared and the calculations revealed the impact of Trp321 on the electronic properties of the heme. Without Trp321 the heme assumed a triradical state with single electrons on the πxy and πyz orbitals of Fe and another on the a2u orbital of the porphyrin ring that can either be coupled with the first two, to assume a quartet state, or decoupled to form a doublet state. With Trp321, however, a transfer of an electron from the πTrp orbital to a2u porphyrin orbital leads to loss of radical character of the porphyrin and leaves the Trp321 group with a radical character. INH was observed to have strong interaction with CpdI and the absence of Trp321 significantly decreased the binding energy by 2 kcal mol-1 explaining the importance of Trp321 in the binding of INH. The results in this study show the importance of Trp321 in the binding of INH and its effect on its electronic properties, which is consistent with previous experimental findings that mutation of Trp321 results in an increase in drug resistance.