Synthesis, Spectroscopic, In-vitro and Computational Analysis of Hydrazones as Potential Antituberculosis Agents: (Part-I)

2020 ◽  
Vol 23 (5) ◽  
pp. 392-401 ◽  
Author(s):  
Bapu R. Thorat ◽  
Deepa Rani ◽  
Ramesh S. Yamgar ◽  
Suraj N. Mali
Keyword(s):  
Electronic Excitation ◽  
Condensation Reaction ◽  
Multidrug Resistant ◽  
Healthcare Sector ◽  
Spectroscopic Techniques ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
In Silico Admet ◽  
Mdr Tb

Background: Since the last few decades, the healthcare sector is facing the problem of the development of multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) infections all over the world. Regardless of the current healthcare progress for the treatment of mycobacterial infections, we are still unable to control addition of every year 9 million new cases of tuberculosis (TB). Objective: We had an objective to synthesize some novel hydrazones, which were further subjected to characterization, Photoluminescence study, in vitro anti-mycobacterium testing and in silico ADMET predictions. Methods: Some new hydrazone derivatives have been successfully prepared by the condensation reaction in the present study. All the compounds were characterized by using FTIR, NMR, UV, Fluorescence spectroscopic techniques. Results: All our newly synthesized compounds showed strong electronic excitation at 292.6 – 319.0 nm and displayed more intense emissions in the 348 – 365 nm regions except compound 3i. The newly synthesized hydrazones 3a, 3b, 3f and 3g were found to be the most active compounds and showed MIC (Minimum inhibitory concentrations) values of 12.5 μg/mL. Conclusion: In the realm of development of more potent, effective, safer and less toxic antituberculosis agents; our current study would definitely help the medicinal chemists to develop potent analogues containing hydrazine motifs in them.

scholarly journals Validation of Cycloserine Efficacy in Treatment of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Beijing, China

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Xia Yu ◽  
Xiling Zeng ◽  
Wenhui Shi ◽  
Yanjie Hu ◽  
Wenjuan Nie ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Multidrug Resistant ◽  
Peak Serum ◽  
Drug Resistant ◽  
Serum Concentrations ◽  
Wild Type ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Mdr Tb

ABSTRACTCycloserine (Cs) is recommended by the World Health Organization as a second-line drug to treat multidrug-resistant tuberculosis (MDR-TB); however, its efficacy has never been sufficiently evaluated. To gain some insights into the value of cycloserine for MDR-TB treatment,in vitrobacteriostatic effect was determined and patient validations were performed prospectively. Thein vitroactivity of Cs against 104 wild-typeMycobacterium tuberculosisstrains was determined, and serum Cs concentrations were measured for 73 MDR TB patients 2 h after administration. The treatment outcomes for 27 MDR-TB patients who had baseline isolates and were treated with Cs-containing regimens were followed up. The MICs for 90% of the recruited 104 wild-type strains were below 32 μg/ml. Eighteen out of 52 patients had peak serum concentrations (Cmax) below 20 μg/ml at the dosage of 500 mg daily, while 13 out of 21 patients had peak serum concentrations higher than 35 μg/ml at the dosage of 750 mg daily. The percentage of favorable treatment outcomes among patients with aCmax/MIC ratio of ≥1 was statistically significantly higher than that among the group with aCmax/MIC ratio of <1 (P= 0.022). The epidemiological cutoff value for Cs susceptibility testing was 32 μg/ml. A high percentage of patients receiving the recommended dosage of 10 mg/kg for Cs administration could not acquire desirable blood concentrations; therefore, adjusting the dosage according to drug concentration monitoring is necessary. TheCmax/MIC ratio might be a good indicator for predicting the treatment outcome for patients with MDR-TB or extensively drug-resistant TB (XDR-TB) who are being administered Cs-containing regimens.

scholarly journals Comparison of In Vitro Activity and MIC Distributions between the Novel Oxazolidinone Delpazolid and Linezolid against Multidrug-Resistant and Extensively Drug-Resistant Mycobacterium tuberculosis in China

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Zhaojing Zong ◽  
Wei Jing ◽  
Jin Shi ◽  
Shu'an Wen ◽  
Tingting Zhang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Novel Mutation ◽  
Multidrug Resistant ◽  
23S Rrna ◽  
Drug Resistant ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Significant Difference ◽  
Mdr Tb

ABSTRACT Oxazolidinones are efficacious in treating mycobacterial infections, including tuberculosis (TB) caused by drug-resistant Mycobacterium tuberculosis. In this study, we compared the in vitro activities and MIC distributions of delpazolid, a novel oxazolidinone, and linezolid against multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) in China. Additionally, genetic mutations in 23S rRNA, rplC, and rplD genes were analyzed to reveal potential mechanisms underlying the observed oxazolidinone resistance. A total of 240 M. tuberculosis isolates were included in this study, including 120 MDR-TB isolates and 120 XDR-TB isolates. Overall, linezolid and delpazolid MIC90 values for M. tuberculosis isolates were 0.25 mg/liter and 0.5 mg/liter, respectively. Based on visual inspection, we tentatively set epidemiological cutoff (ECOFF) values for MIC determinations for linezolid and delpazolid at 1.0 mg/liter and 2.0 mg/liter, respectively. Although no significant difference in resistance rates was observed between linezolid and delpazolid among XDR-TB isolates (P > 0.05), statistical analysis revealed a significantly greater proportion of linezolid-resistant isolates than delpazolid-resistant isolates within the MDR-TB group (P = 0.036). Seven (53.85%) of 13 linezolid-resistant isolates were found to harbor mutations within the three target genes. Additionally, 1 isolate exhibited an amino acid substitution (Arg126His) within the protein encoded by rplD that contributed to high-level resistance to linezolid (MIC of >16 mg/liter), compared to a delpazolid MIC of 0.25. In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity was comparable to that of linezolid. A novel mutation within rplD that endowed M. tuberculosis with linezolid, but not delpazolid, resistance was identified.

scholarly journals In Vitro Antimycobacterial Activity of Pakistani Beri Honey Using BACTEC MGIT 960

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Abdul Hannan ◽  
Saira Munir ◽  
Muhammad Usman Arshad ◽  
Nabila Bashir
Keyword(s):  
Growth Control ◽  
Antimycobacterial Activity ◽  
Multidrug Resistant ◽  
Bacterial Disease ◽  
First Line ◽  
Development Of Resistance ◽  
Extensively Drug Resistant ◽  
Mdr Tb ◽  
Growth Controls

Background. Tuberculosis (TB) is a chronic bacterial disease. Mycobacterium tuberculosis, being the leading member of the MTB complex, is the main cause of tuberculosis worldwide. Tuberculosis is managed with combination of drugs: streptomycin, isoniazid, rifampicin, ethambutol, and pyrazinamide. Over the recent past years resistance against first line antituberculous drugs has emerged rapidly throughout the world resulting in MDR strains. The new threat in the management of MDR-TB is the development of resistance against second line drugs: aminoglycosides, polypeptides, fluoroquinolones, and thioamides. Multidrug resistant (MDR) and extensively drug resistant TB (XDR) strains have become a major concern to control TB particularly in the developing countries. The need of the hour is to look for new modalities having antimycobacterial activity. Honey has been well known for its antibacterial activity. We intended to explore its antimycobacterial activity against MDR-TB. Objective. The objective of this study was to determine whether Pakistani Beri honey has any antimycobacterial activity. Method. The study was conducted in the Department of Microbiology, University of Health Sciences, Lahore. Clinical isolates (n=21) of MDR-MTB were evaluated for their susceptibility to Beri honey. The isolates were provided, courtesy of Pakistan Medical Research Council. These isolates were identified by MTBc ID test (Becton & Dickinson) and further tested for their antimycobacterial activity using Beri honey. The honey was tested at the following concentrations (v/v): 1%, 2%, 3%, 4%, and 5% in MGIT 960. Growth controls were also inoculated with each isolate (growth control has no concentration of honey, only containing growth of isolate). Results. MDR-TB isolates (n=21) were tested; 3 (14%) isolates were susceptible at 1% v/v honey, while at 2% v/v of honey 18 (86%) isolates were found to be susceptible. All the 21 isolates (n=21) were susceptible at 3% v/v of honey. Conclusion. The present study clearly demonstrates that Pakistani Beri honey possesses significant antimycobacterial activity in vitro. The antimycobacterial activity of Pakistani Beri honey may, therefore, be exploited in an appropriate mouse model.

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.

scholarly journals Synthesis, Characterization and Antituberculosis Activity of Biologically Nanostructured Zinc and Titanium Metal Compounds

2020 ◽  
Vol 32 (6) ◽  
pp. 1286-1290
Author(s):  
Savita Belwal ◽  
Sujana Kariveda ◽  
Saritha Ramagiri
Keyword(s):  
Multidrug Resistant ◽  
Metal Compounds ◽  
Zinc Compounds ◽  
Macrotyloma Uniflorum ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Transmission Electron ◽  
H37rv Strain ◽  
Mdr Tb

Green chemistry was used to obtain nano-range sized titanium and zinc compounds from their macro-sizes by using an aqueous extract of horse gram (Macrotyloma uniflorum). Ultraviolet-visible (UV-vis) and Fourier-transform infrared (FTIR) spectrophotometers were employed for characterizing the nanoparticles of biosynthesized metal nanoparticles. Transmission electron microscopy (TEM) was used to analyse the reduced nanoparticles of Ti and Zn metals. Microdilution was employed to determine in vitro properties, such as effects of nanocomplex antimicrobials on Mycobacterium tuberculosis (MTB) H37RV strain. MTB strains isolated from patients with multidrug-resistant tuberculosis (MDR-TB) were resistant to first-line drugs. Novel synthesized nano-complexes exhibited potential antituberculosis activities. Titanium nanocomplexes exhibited the highest minimal inhibitory concentration (MIC) in comparison to zinc nanocomplex. In a cytotoxic study, an IC50 of 1000 μg/mL, for both Ti and Zn nanocomplexes, was reported, and thus, these complexes were non-toxic when compared to isoniazid.

scholarly journals Draft Genome Sequences of Two Drug-Resistant Mycobacterium tuberculosis Isolates from Myanmar

2016 ◽  
Vol 4 (5) ◽  
Author(s):  
Htin Lin Aung ◽  
Thanda Tun ◽  
Elizabeth Permina ◽  
Wint Wint Nyunt ◽  
Si Thu Aung ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Draft Genome ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Genome Sequences ◽  
Health Concerns ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Mdr Tb

Multidrug-resistant tuberculosis (MDR-TB) and lately, extensively drug-resistant TB (XDR-TB) are increasing global health concerns. Here, we present the genome sequences of two MDR-TB isolates from Myanmar, one of 27 countries with a high MDR-TB burden, and describe a number of mutations consistent with these being XDR-TB isolates.

scholarly journals Evolving rifampicin and isoniazid mono-resistance in a high multidrug-resistant and extensively drug-resistant tuberculosis region: a retrospective data analysis

BMJ Open ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. e031663
Author(s):  
Nomonde Ritta Mvelase ◽  
Yusentha Balakrishna ◽  
Keeren Lutchminarain ◽  
Koleka Mlisana
Keyword(s):  
South Africa ◽  
Diagnostic Algorithm ◽  
Multidrug Resistant ◽  
Continuous Phase ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Kwazulu Natal ◽  
Mdr Tb

ObjectivesSouth Africa ranks among the highest drug-resistant tuberculosis (DR-TB) burdened countries in the world. This study assessed the changes in resistance levels in culture confirmed Mycobacterium tuberculosis (MTB) in the highest burdened province of South Africa during a period where major changes in diagnostic algorithm were implemented.SettingThis study was conducted at the central academic laboratory of the KwaZulu-Natal province of South Africa.ParticipantsWe analysed data for all MTB cultures performed in the KwaZulu-Natal province between 2011 and 2014. The data were collected from the laboratory information system.ResultsOut of 88 559 drug susceptibility results analysed, 18 352 (20.7%) were resistant to rifampicin (RIF) and 19 190 (21.7%) showed resistance to isoniazid (INH). The proportion of rifampicin resistant cases that were mono-resistant increased from 15.3% in 2011 to 21.4% in 2014 while INH mono-resistance (IMR) showed a range between 13.8% and 21.1%. The multidrug-resistant tuberculosis (MDR-TB) rates increased from 18.8% to 23.9% and the proportion of MDR-TB cases that had extensively drug-resistant tuberculosis remained between 10.2% and 11.1%. Most drug resistance was found in females between the ages of 15 and 44 years and the northern districts bordering high MDR-TB regions had the highest MDR-TB rates.ConclusionOur findings show increasing RIF mono-resistance (RMR) and a substantial amount of IMR. This highlights a need for an initial test that detects resistance to both these drugs so as to avoid using RIF monotherapy during continuous phase of treatment in patients with IMR. Furthermore, addition of INH will benefit patients with RMR. Although DR-TB is widespread, HIV and migration influence its distribution; therefore, TB control strategies should include interventions that target these aspects.

scholarly journals In VitroActivity of β-Lactams in Combination with β-Lactamase Inhibitors against Multidrug-Resistant Mycobacterium tuberculosis Isolates

2015 ◽  
Vol 60 (1) ◽  
pp. 393-399 ◽  
Author(s):  
Dan Zhang ◽  
Yufeng Wang ◽  
Jie Lu ◽  
Yu Pang
Keyword(s):  
Synergistic Effect ◽  
Multidrug Resistant ◽  
Nucleotide Substitutions ◽  
Single Nucleotide ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Amoxicillin Clavulanate ◽  
Increased Susceptibility

ABSTRACTThe combination of β-lactams and β-lactamase inhibitors has been shown to have potentin vitroactivity against multidrug-resistant tuberculosis (MDR-TB) isolates. In order to identify the most potent β-lactam–β-lactamase inhibitor combination against MDR-TB, we selected nine β-lactams and three β-lactamase inhibitors, which belong to different subgroups. A total of 121 MDR-TB strains were included in this study. Out of the β-lactams used herein, biapenem was the most effective against MDR-TB and had an MIC50value of 8 μg/ml. However, after the addition of clavulanate or sulbactam, meropenem exhibited the most potent anti-MDR-TB activity with an MIC50value of 4 μg/ml. For meropenem, 76 (62.8%), 41 (33.9%), and 22 (18.2%) of the 121 MDR-TB strains were subjected to a synergistic effect when the drug was combined with sulbactam, tazobactam, or clavulanate, respectively. Further statistical analysis revealed that significantly more strains experienced a synergistic effect when exposed to the combination of meropenem with sulbactam than when exposed to meropenem in combination with tazobactam or clavulanate, respectively (P< 0.01). In addition, a total of 10.7% (13/121) of isolates harbored mutations in theblaCgene, with two different nucleotide substitutions: AGT333AGG and ATC786ATT. For the strains with a Ser111Arg substitution in BlaC, a better synergistic effect was observed in the meropenem-clavulanate and in the amoxicillin-clavulanate combinations than that in a synonymous single nucleotide polymorphism (SNP) group. In conclusion, our findings demonstrate that the combination of meropenem and sulbactam shows the most potent activity against MDR-TB isolates. In addition, the Ser111Arg substitution of BlaC may be associated with an increased susceptibility of MDR-TB isolates to meropenem and amoxicillin in the presence of clavulanate.

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.

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