Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

Hu, Yan; Xu, Li; He, Yang; Lü, Nan; Liu, J; Shen, Jing; Zhu, Damian; Feng, Xin; Wang, Y W; Chun, Yang

doi:10.1155/2017/4563826

Cited by 17 publications

(13 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present findings revealed that 48.2% (124/257) were resistant to at least one five SLD. Previously, several studies reported the resistance rate of SLD strains has been estimated to range from 25.7 to 51.9% (Bakuła et al, 2016; Brossier et al, 2017; Hu et al, 2017). According to a recently published World Health Organization (WHO) report, among cases of MDR-TB in 2017, 8.5% ( 95%CI , 6.2–11.0%) were estimated to have XDR-TB (World Health Organization [WHO], 2018).…”

Section: Discussionmentioning

confidence: 99%

Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China

Gao

Zhang

et al. 2019

Front. Microbiol.

View full text Add to dashboard Cite

The emergence of drug-resistant tuberculosis (TB) is involved in ineffective treatment of TB, especially multidrug resistant/extensively resistant TB (MDR/XDR-TB), leading to acquired resistance and transmission of drug-resistant strains. Second-line drugs (SLD), including both fluoroquinolones and injectable drugs, were commonly proved to be the effective drugs for treatment of drug-resistant TB. The purpose of this study was to investigate the prevalence of SLD-resistant strains and its specific mutations in drug-resistant Mycobacterium tuberculosis clinical isolates, and to acknowledge the transmission pattern of SLD resistance strains in Hebei. The genes gyrA , gyrB , rrs , eis promoter and tlyA of 257 drug-resistant clinical isolates were sequenced to identify mutations that could be responsible for resistance against fluoroquinolones and second-line injectable drugs. Each isolate was genotyped by Spoligotyping and 15-loci MIRU-VNTR. Our results indicated that 48.2% isolates were resistant to at least one of five SLD. Of them, 37.7% isolates were resistant to fluoroquinolones and 24.5% isolates were resistant to second-line injectable drugs. Mutations in genes gyrA , gyrB , rrs , eis promoter and tlyA were detected in 73 (75.3%), 7 (7.2%), 24 (38.1%), 5 (7.9%), and 3 (4.8%) isolates, respectively. The most prevalent mutations were the D94G (23.7%) in gyrA gene and the A1401G (33.3%) in rrs gene. A combination of gyrA , rrs and eis promoter can act as a valuable predicator for predicting XDR phenotype. These results highlight the development of rapid diagnosis are the effective manners for the control of SLD-TB or XDR-TB.

show abstract

Section: Discussionmentioning

confidence: 99%

Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China

Gao

Zhang

et al. 2019

Front. Microbiol.

View full text Add to dashboard Cite

show abstract

“…2 The emergence of multidrug-resistant TB (MDR-TB) 3 and extensively drug-resistant tuberculosis (XDR-TB) 4 has made the battle against TB more difficult because most currently available therapeutic options are ineffective against these resistant strains. 5 Furthermore, the appearance of totally drug-resistant (TDR) strains has heightened this challenge because these strains are unaffected by the currently available anti-TB agents. 6 Thus, developing novel therapeutic agents that are capable of combating resistant strains of MTB is necessary.…”

Section: Introductionmentioning

confidence: 99%

In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against Mycobacterium tuberculosis

Venugopala¹,

Tratrat²,

Pillay³

et al. 2020

DDDT

View full text Add to dashboard Cite

Background and Purpose: Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors. Methods: The title compounds (1a-d) and (2a-b) were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry's Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed. Results: Of the compounds tested for anti-TB activity, pyrimidinone 1a and pyrimidinethione 2a displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound 2a was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds 1a and 2a. Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds. Conclusion: Pyrimidinone 1a and pyrimidinethione 2a were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.

show abstract

“…The increasing prevalence of TB in the form of multi-drug-resistant (MDR)-TB [ 2 ] and extensively drug-resistant (XDR)-TB [ 3 ] has triggered the necessity for more effective therapeutic regimens with fewer side effects. Treating and managing MDR-TB and XDR-TB has proven to be more challenging, as second-line drugs have largely become less effective [ 4 ]. This problem has been made worse by the emergence of totally drug-resistant (TDR) strains of MTB [ 5 ], which do not respond to anti-TB drug treatments.…”

Section: Introductionmentioning

confidence: 99%

Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics

et al. 2020

View full text Add to dashboard Cite

In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl)-4H-1,2,4-triazole-3-thiol (1) and its Schiff bases 2, 3, and 4 were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by resazurin microtiter assay (REMA) plate method. Test compound 1 exhibited promising anti-TB activity against H37Rv and MDR strains of MTB at 5.5 µg/mL and 11 µg/mL, respectively. An attempt to identify the suitable molecular target for compound 1 was performed using a set of triazole thiol cellular targets, including β-ketoacyl carrier protein synthase III (FABH), β-ketoacyl ACP synthase I (KasA), CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, and N-acetylglucosamine-1-phosphate uridyltransferase. MTB β-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound 1 via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound 1 compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound 1 involves the formation of hydrogen bonding with the catalytic histidine residues, and it also impedes access of fatty-acid substrates to the active site through interference with α5–α6 helix movement. Test compound 1-specific structural changes at the ALA274–ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound 1 when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site.

show abstract

Prevalence and Molecular Characterization of Second-Line Drugs Resistance among Multidrug-ResistantMycobacterium tuberculosisIsolates in Southwest of China

Cited by 17 publications

References 30 publications

Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China

Mutation and Transmission Profiles of Second-Line Drug Resistance in Clinical Isolates of Drug-Resistant Mycobacterium tuberculosis From Hebei Province, China

<p>In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against <em>Mycobacterium tuberculosis</em></p>

Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4H-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics

Contact Info

Product

Resources

About