scholarly journals Mechanism of thioamide drug action against tuberculosis and leprosy

2007 ◽  
Vol 204 (1) ◽  
pp. 73-78 ◽  
Author(s):  
Feng Wang ◽  
Robert Langley ◽  
Gulcin Gulten ◽  
Lynn G. Dover ◽  
Gurdyal S. Besra ◽  
...  
Keyword(s):  
Tight Binding ◽  
Multidrug Resistant ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Definitive Evidence ◽  
Target Drug ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
A Cell ◽  
Covalent Adducts

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target–drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

scholarly journals Emergence of Low-level Delamanid and Bedaquiline Resistance During Extremely Drug-resistant Tuberculosis Treatment

2019 ◽  
Vol 69 (7) ◽  
pp. 1229-1231 ◽  
Author(s):  
Silke Polsfuss ◽  
Sabine Hofmann-Thiel ◽  
Matthias Merker ◽  
David Krieger ◽  
Stefan Niemann ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
New Drugs ◽  
Tuberculosis Treatment ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Low Level ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant

Abstract Two new drugs, delamanid and bedaquiline, have recently been approved for treatment of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis. Here, we report a case of clofazimine, bedaquiline, and low-level delamanid resistances acquired during treatment of a patient with XDR tuberculosis.

scholarly journals Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Children: The Role of Bedaquiline and Delamanid

2021 ◽  
Vol 9 (5) ◽  
pp. 1074
Author(s):  
Francesco Pecora ◽  
Giulia Dal Canto ◽  
Piero Veronese ◽  
Susanna Esposito
Keyword(s):  
Adverse Effects ◽  
Pediatric Population ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Standard Regimen ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Mdr Tb

Multidrug-resistant (MDR) tuberculosis (TB) has been emerging at an alarming rate over the last few years. It has been estimated that about 3% of all pediatric TB is MDR, meaning about 30,000 cases each year. Although most children with MDR-TB can be successfully treated, up to five years ago effective treatment was associated with a high incidence of severe adverse effects and patients with extensively drug-resistant (XDR) TB had limited treatment options and no standard regimen. The main objective of this manuscript is to discuss our present knowledge of the management of MDR- and XDR-TB in children, focusing on the characteristics and available evidence on the use of two promising new drugs: bedaquiline and delamanid. PubMed was used to search for all of the studies published up to November 2020 using key words such as “bedaquiline” and “delamanid” and “children” and “multidrug-resistant tuberculosis” and “extensively drug-resistant tuberculosis”. The search was limited to articles published in English and providing evidence-based data. Although data on pediatric population are limited and more studies are needed to confirm the efficacy and safety of bedaquiline and delamanid, their use in children with MDR-TB/XDR-TB appears to have good tolerability and efficacy. However, more evidence on these new anti-TB drugs is needed to better guide their use in children in order to design effective shorter regimens and reduce adverse effects, drug interactions, and therapeutic failure.

scholarly journals Effectiveness and safety of delamanid- or bedaquiline-containing regimens among children and adolescents with multidrug resistant or extensively drug resistant tuberculosis: A nationwide study from Belarus, 2015-19

2021 ◽  
Vol 91 (1) ◽  
Author(s):  
Varvara Solodovnikova ◽  
Ajay M.V. Kumar ◽  
Hennadz Hurevich ◽  
Yuliia Sereda ◽  
Vera Auchynka ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Multidrug Resistant ◽  
Post Treatment ◽  
New Drugs ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Mdr Tb ◽  
Culture Conversion

There is limited evidence describing the safety and effectiveness of bedaquiline and delamanid containing regimens in children and adolescents with Multidrug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) globally. In this nationwide descriptive cohort study from Belarus, we examined adverse drug events, time to culture conversion, treatment outcomes including post-treatment recurrence among children and adolescents (<18 years of age) treated with bedaquiline and/or delamanid containing regimens from 2015 to 2019. Of the 40 participants included (55% females; age range 10-17 years), 20 (50%) had XDR-TB and 15 (38%) had resistance to either fluoroquinolone or second-line injectable. Half of the patients received delamanid and another half received bedaquiline with one patient receiving both drugs. AEs were reported in all the patients. A total of 224 AEs were reported, most of which (76%) were mild in nature. Only 10 (5%) AEs were graded severe and one AE was graded life-threatening. A total of 7 AEs (3%) were classified as ‘serious’ and only one patient required permanent discontinuation of the suspected drug (linezolid). Most of the AEs (94%) were resolved before the end of treatment. All patients culture-positive at baseline (n=34) became culture-negative within three months of treatment. Median time to culture conversion was 1.1 months (interquartile range: 0.9-1.6). Two patients were still receiving treatment at the time of analysis. The remaining 38 patients successfully completed treatment. Among those eligible and assessed at 6 (n=32) and 12 months (n=27) post-treatment, no recurrences were detected. In conclusion, treatment of children and adolescents with MDR-TB and XDR-TB using bedaquiline and/or delamanid containing regimens was effective and had favourable safety profile. Achieving such excellent outcomes under programmatic settings is encouraging for other national tuberculosis programmes, which are in the process of introducing or scaling-up the use of these new drugs in their countries.

Antimicrobial Peptides and their Multiple Effects at Sub-Inhibitory Concentrations

2020 ◽  
Vol 20 (14) ◽  
pp. 1264-1273 ◽  
Author(s):  
Bruno Casciaro ◽  
Floriana Cappiello ◽  
Walter Verrusio ◽  
Mauro Cacciafesta ◽  
Maria Luisa Mangoni
Keyword(s):  
Antimicrobial Peptides ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Lead Compounds ◽  
Bacterial Pathogenicity ◽  
Growth Inhibitory ◽  
Resistant Strains ◽  
Conventional Antibiotics

The frequent occurrence of multidrug-resistant strains to conventional antimicrobials has led to a clear decline in antibiotic therapies. Therefore, new molecules with different mechanisms of action are extremely necessary. Due to their unique properties, antimicrobial peptides (AMPs) represent a valid alternative to conventional antibiotics and many of them have been characterized for their activity and cytotoxicity. However, the effects that these peptides cause at concentrations below the minimum growth inhibitory concentration (MIC) have yet to be fully analyzed along with the underlying molecular mechanism. In this mini-review, the ability of AMPs to synergize with different antibiotic classes or different natural compounds is examined. Furthermore, data on microbial resistance induction are reported to highlight the importance of antibiotic resistance in the fight against infections. Finally, the effects that sub-MIC levels of AMPs can have on the bacterial pathogenicity are summarized while showing how signaling pathways can be valid therapeutic targets for the treatment of infectious diseases. All these aspects support the high potential of AMPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities.

scholarly journals Tuberculose Multirresistente por Estirpes da Família Beijing, em Doentes de Lisboa, Portugal: Estudo Preliminar

2017 ◽  
Vol 30 (3) ◽  
pp. 175 ◽  
Author(s):  
Fernando Maltez ◽  
Teresa Martins ◽  
Diana Póvoas ◽  
João Cabo ◽  
Helena Peres ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Past History ◽  
Multidrug Resistant ◽  
Resistance Pattern ◽  
Drug Resistant ◽  
Beijing Family ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Number Of Patients ◽  
Drug Resistant Strains

Introduction: Beijing family strains of Mycobacterium tuberculosis are associated with multidrug-resistance. Although strains of the Lisboa family are the most common among multidrug-resistant and extensively drug-resistant patients in the region, several studies have reported the presence of the Beijing family. However, the features of patients from whom they were isolated, are not yet known.Material and Methods: Retrospective study involving 104 multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, from the same number of patients, isolated and genotyped between 1993 and 2015 in Lisbon. We assessed the prevalence of strains of both families and the epidemiologic and clinical features of those infected with Beijing family strains.Results: Seventy-four strains (71.2%) belonged to the Lisboa family, 25 (24.0%) showed a unique genotypic pattern and five (4.8%) belonged to the Beijing family, the latter identified after 2009. Those infected with Beijing family strains were angolan (n = 1), ukrainian (n = 2) and portuguese (n = 2), mainly young-aged and, four of five immunocompetent and with no past history of tuberculosis. All had multidrug-resistant tuberculosis. We did not find any distinctive clinical or radiological features, neither a predominant resistance pattern. Cure rate was high (four patients).Discussion: Although the number of infected patients with Beijing strains was small, it suggests an important proportion of primary tuberculosis, a potential for transmission in the community but also a better clinical outcome when compared to other reported strains, such as W-Beijing and Lisboa.Conclusion: Although Lisboa family strains account for most of the multidrug and extensively drug-resistant tuberculosis cases in Lisbon area, Beijing strains are transmitted in the city and might change the local characteristics of the epidemics.

scholarly journals Tuberculosis Incidence Trends from 1990 to 2017 Highlight Impact of Drug Resistance: Results from the Global Burden of Disease Study

2020 ◽  
Author(s):  
Zejin Ou ◽  
Wenqiao He ◽  
Danfeng Yu ◽  
Yongzhi Li ◽  
Yuanhao Liang ◽  
...  
Keyword(s):  
Burden Of Disease ◽  
Multidrug Resistant ◽  
Global Burden Of Disease ◽  
Global Burden ◽  
Incidence Trends ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Mdr Tb ◽  
Disease Study ◽  
Increasing Trends

Abstract Objectives This study aimed to determine the global incidence trends of tuberculosis (TB) from 1990 to 2017.Methods Data was obtained from the Global Burden of Disease (GBD) study. The estimated annual percentage changes (EAPCs) were calculated with the age-standardised incidence rate (ASIR) to estimate trends in incidence of TB, including multidrug-resistant TB (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB).Results Globally, the number of TB cases was 8965.81×103 in 2017, with a 9.42% increase since 1990. The ASIR for TB showed a decreasing trend from 1990 to 2017 (EAPC = −1.19, 95% confidence interval [CI]: −1.32 to −1.07). Meanwhile, decreasing trends were observed in 162 countries/territories, particularly in Ethiopia and China where EAPCs were −4.51 (95%CI: −5.22 to −3.80) and −4.21 (95%CI: −4.98 to −3.44), respectively. However, obvious increasing trends of MDR-TB cases occurred in areas with low and low-middle sociodemographic indexes (SDI), with EAPCs of 7.97 (95%CI: 2.47 to 13.75) and 6.30 (95%:1.17 to 11.68), respectively. The ASIR for XDR-TB showed pronounced increasing trends globally from 1991 to 2017, with an EAPC of 11.74 (95%CI: 7.50 to 16.16). The largest rising trends of XDR-TB were observed in Kyrgyzstan (EAPC = 31.06, 95%CI: 23.07 to 39.57), followed by Azerbaijan and Uzbekistan.Conclusions There was a decreasing trend for TB incidence worldwide, although it was more pronounced in specific countries and regions. However, the rapidly rising trends of MDR-TB and XDR-TB cases in low and low-middle SDI areas and countries may have an adverse impact on the global control of TB.

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