scholarly journals Role of embB Codon 306 Mutations in Mycobacterium tuberculosis Revisited: a Novel Association with Broad Drug Resistance and IS6110 Clustering Rather than Ethambutol Resistance

2005 ◽  
Vol 49 (9) ◽  
pp. 3794-3802 ◽  
Author(s):  
Manzour Hernando Hazbón ◽  
Miriam Bobadilla del Valle ◽  
Marta Inírida Guerrero ◽  
Mandira Varma-Basil ◽  
Ingrid Filliol ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Odds Ratio ◽  
Univariate Analysis ◽  
Drug Susceptibility ◽  
Drug Resistant ◽  
Development Of Resistance ◽  
Resistance Patterns ◽  
Novel Association

ABSTRACT Mutations at position 306 of embB (embB306) have been proposed as a marker for ethambutol resistance in Mycobacterium tuberculosis; however, recent reports of embB306 mutations in ethambutol-susceptible isolates caused us to question the biological role of this mutation. We tested 1,020 clinical M. tuberculosis isolates with different drug susceptibility patterns and of different geographical origins for associations between embB306 mutations, drug resistance patterns, and major genetic group. One hundred isolates (10%) contained a mutation in embB306; however, only 55 of these mutants were ethambutol resistant. Mutations in embB306 could not be uniquely associated with any particular type of drug resistance and were found in all three major genetic groups. A striking association was observed between these mutations and resistance to any drug (P < 0.001), and the association between embB306 mutations and resistance to increasing numbers of drugs was highly significant (P < 0.001 for trend). We examined the association between embB306 mutations and IS6110 clustering (as a proxy for transmission) among all drug-resistant isolates. Mutations in embB306 were significantly associated with clustering by univariate analysis (odds ratio, 2.44; P = 0.004). In a multivariate model that also included mutations in katG315, katG463, gyrA95, and kasA269, only mutations in embB306 (odds ratio, 2.14; P = 0.008) and katG315 (odds ratio, 1.99; P = 0.015) were found to be independently associated with clustering. In conclusion, embB306 mutations do not cause classical ethambutol resistance but may predispose M. tuberculosis isolates to the development of resistance to increasing numbers of antibiotics and may increase the ability of drug-resistant isolates to be transmitted between subjects.

scholarly journals Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis

2007 ◽  
Vol 51 (7) ◽  
pp. 2618-2620 ◽  
Author(s):  
Xin Shen ◽  
Guo-miao Shen ◽  
Jie Wu ◽  
Xiao-hong Gui ◽  
Xia Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Odds Ratio ◽  
Rapid Detection ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Candidate Marker ◽  
Resistant Tuberculosis

ABSTRACT embB306 mutants were detected in both ethambutol (EMB)-resistant and EMB-susceptible strains of Mycobacterium tuberculosis. Multidrug-resistant (MDR) strains had a higher proportion of embB306 mutants than non-MDR strains (odds ratio, 6.78; P < 0.001). The embB306 locus is a candidate marker for rapid detection of MDR and extremely drug resistant tuberculosis.

scholarly journals Signatures of Selection at Drug Resistance Loci in Mycobacterium tuberculosis

mSystems ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
Tatum D. Mortimer ◽  
Alexandra M. Weber ◽  
Caitlin S. Pepperell
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Natural Populations ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Tb Treatment ◽  
Significant Burden ◽  
Resistance Patterns ◽  
Signatures Of Selection ◽  
Selection For

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a significant burden on global health. Antibiotic treatment imposes strong selective pressure on M. tuberculosis populations. Identifying the mutations that cause drug resistance in M. tuberculosis is important for guiding TB treatment and halting the spread of drug resistance. Whole-genome sequencing (WGS) of M. tuberculosis isolates can be used to identify novel mutations mediating drug resistance and to predict resistance patterns faster than traditional methods of drug susceptibility testing. We have used WGS from natural populations of drug-resistant M. tuberculosis to characterize effects of selection for advantageous mutations on patterns of diversity at genes involved in drug resistance. The methods developed here can be used to identify novel advantageous mutations, including new resistance loci, in M. tuberculosis and other clonal pathogens.

scholarly journals Molecular characterization and drug resistance patterns of Mycobacterium tuberculosis complex in extrapulmonary tuberculosis patients in Addis Ababa, Ethiopia

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243493
Author(s):  
Getu Diriba ◽  
Abebaw Kebede ◽  
Habteyes Hailu Tola ◽  
Bazezew Yenew ◽  
Shewki Moga ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Molecular Characterization ◽  
Addis Ababa ◽  
Extrapulmonary Tuberculosis ◽  
Strain Identification ◽  
Molecular Characteristics ◽  
Drug Resistant ◽  
Resistance Patterns ◽  
Mdr Tb

Background Molecular characterization of Mycobacterium tuberculosis (MTB) is important to understand the pathogenesis, diagnosis, treatment, and prevention of tuberculosis (TB). However, there is limited information on molecular characteristics and drug-resistant patterns of MTB in patients with extra-pulmonary tuberculosis (EPTB) in Ethiopia. Thus, this study aimed to determine the molecular characteristics and drug resistance patterns of MTB in patients with EPTB in Addis Ababa, Ethiopia. Methods This study was conducted on frozen stored isolates of EPTB survey conducted in Addis Ababa, Ethiopia. A drug susceptibility test was performed using BACTEC-MGIT 960. Species and strain identification were performed using the Geno-Type MTBC and spoligotyping technique, respectively. Data were entered into the MIRU-VNTRplus database to assess the spoligotype patterns of MTB. Analysis was performed using SPSS version 23, and participants’ characteristics were presented by numbers and proportions. Results Of 151 MTB isolates, 29 (19.2%) were resistant to at least one drug. The highest proportion of isolates was resistant to Isoniazid (14.6%) and Pyrazinamide (14.6%). Nine percent of isolates had multidrug-resistant TB (MDR-TB), and 21.4% of them had pre-extensively drug-resistant TB (pre-XDR-TB). Among the 151 MTB isolates characterized by spoligotyping, 142 (94.6%) had known patterns, while 9 (6.0%) isolates were not matched with the MIRU-VNTRplus spoligotype database. Of the isolates which had known patterns, 2% was M.bovis while 98% M. tuberculosis. Forty-one different spoligotype patterns were identified. The most frequently identified SpolDB4 (SIT) wereSIT149 (21.2%), SIT53 (14.6%) and SIT26 (9.6%). The predominant genotypes identified were T (53.6%), Central Asia Strain (19.2%) and Haarlem (9.9%). Conclusion The present study showed a high proportion of MDR-TB and pre-XDR-TB among EPTB patients. The strains were mostly grouped into SIT149, SIT53, and SIT26. The T family lineage was the most prevalent genotype. MDR-TB and pre-XDR-TB prevention is required to combat these strains in EPTB. A large scale study is required to describe the molecular characteristics and drug resistance patterns of MTB isolates in EPTB patients.

Simultaneous detection of drug-resistant mutations in Mycobacterium tuberculosis and determining their role through in silico docking

2020 ◽  
Vol 20 ◽  
Author(s):  
Somanna Nachappa ◽  
Sumana Neelambike ◽  
Ahmad Sarikhani ◽  
Nallur Ramachandra
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Dna Sequencing ◽  
In Silico ◽  
Sequence Data ◽  
Simultaneous Detection ◽  
Fluoroquinolone Resistance ◽  
Drug Resistant ◽  
In Silico Docking

: A molecular method for diagnosis of drug-resistant Tuberculosis is Multiplex allele-specific PCR (MAS-PCR), which is more time-efficient. Also, understanding the role of mutations when translated to protein, in causing resistance helps better drug designing. Aims: To study MAS-PCR in the detection of drug resistance in comparison to DNA sequencing, and understand the mechanism of interaction of drugs with mutant proteins in Mycobacterium tuberculosis. Methods: Detection of drug-resistant mutations using MAS-PCR and validation through DNA sequencing. MAS-PCR targeted four genes, iniA for the drug Ethambutol, rpsL and rrs for Streptomycin, and gyrA for Fluoroquinolone resistance, respectively. Further, the sequence data was analysed and modelled to study the effect on interaction of the anti-TB drug molecule with the target protein using in silico docking. Results: We identified drug-resistant mutations in four out of 95 isolates with one of them carrying a mutation at codon iniA501, two at gyrA94, and one for both iniA501 and gyrA94 using MAS-PCR. DNA sequencing confirmed drug-resistant mutations in only two isolates, whereas two others had mutation adjacent to the target allele. Molecular docking showed Estimated Free Energy of Binding (ΔG) being higher for Fluoroquinolone binding with GyrA D94V mutant. Both, wild and mutant IniA interact with EMB but had no significant effect on binding energy. Conclusions: DNA sequencing-based drug resistance detection of TB is more accurate than MAS-PCR. Understanding the role of mutations in influencing the drug-protein interaction will help in designing effective drug alternatives.

scholarly journals Prevalence of Multi-Drug Resistant Mycobacterium Tuberculosis in Khyber Pakhtunkhwa – A High Tuberculosis Endemic Area of Pakistan

2020 ◽  
Vol 69 (2) ◽  
pp. 133-137 ◽  
Author(s):  
SAJID ALI ◽  
MUHAMMAD TAHIR KHAN ◽  
ANWAR SHEED KHAN ◽  
NOOR MOHAMMAD ◽  
MUHAMMAD MUMTAZ KHAN ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Simple Random Sampling ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Drug Resistant ◽  
Khyber Pakhtunkhwa ◽  
Mdr Tb

Anti-tuberculosis therapy involves the combination of drugs to hamper the growth of Mycobacterium tuberculosis (MTB). The emergence of multidrug-resistant tuberculosis (MDR-TB) is a global concern. Pakistan has been ranked 5th position in terms of a high burden of MDR-TB in the world. The aim of the current study was to investigate the prevalence of drug resistance in MTB in Khyber Pakhtunkhwa. Random samples were collected from 25 districts using the simple random sampling formula. All samples were processed in a biosafety level 3 laboratory for culture and drug susceptibility testing. Among 5759 presumptive tuberculosis (TB) cases, 1969 (34%) were positive. The proportion of TB was higher in females (39%) than males (29%), thus it represents a significant association between gender and tuberculosis (p < 0.05). People ages between 25 to 34 years were more likely to be infected with MTB (40%). Drug-resistant profile showed 97 (4.9%) patients were infected with MDR-TB. Streptomycin resistance was the highest and was observed in 173 (9%) isolates followed by isoniazid in 119 (6%) isolates. The lowest resistance was observed to pyrazinamide (3%). The prevalence of MDR-TB (10.4%) among patients that previously received anti-tuberculosis treatment is seemingly high. A large-scale drug resistance survey is required to evaluate the drug resistance for better management of tuberculosis.

scholarly journals Whole-genome sequence analysis and comparisons between drug-resistance mutations and minimum inhibitory concentrations of Mycobacterium tuberculosis isolates causing M/XDR-TB

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244829
Author(s):  
Ditthawat Nonghanphithak ◽  
Orawee Kaewprasert ◽  
Pratchakan Chaiyachat ◽  
Wipa Reechaipichitkul ◽  
Angkana Chaiprasert ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Tb 34 ◽  
Susceptibility Tests

Drug resistance (DR) remains a major challenge for tuberculosis (TB) control. Whole-genome sequencing (WGS) provides the highest genetic resolution for genotypic drug-susceptibility tests (DST). We compared DST profiles of 60 Mycobacterium tuberculosis isolates which were drug resistant according to agar proportion tests (one poly DR-TB, 34 multidrug-resistant TB and 25 extensively drug-resistant TB). We additionally performed minimum inhibitory concentration (MIC) tests using Sensititre MYCOTBI plates (MYCOTB) and a WGS-based DST. Agreement between WGS-based DST and MYCOTB was high for all drugs except ethambutol (65%) and ethionamide (62%). Isolates harboring the -15 c/t inhA promoter mutation had a significantly lower MIC for isoniazid than did isolates with the katG Ser315Thr mutation (p < 0.001). Similar patterns were seen for ethambutol (embB Gly406Asp vs. embB Met306Ile), streptomycin (gid Gly73Ala vs. rpsL Lys43Arg), moxifloxacin (gyrA Ala90Val vs. gyrA Asp94Gly) and rifabutin (rpoB Asp435Phe/Tyr/Val vs. rpoB Ser450Leu). For genotypic heteroresistance, isolates with lower proportion of mapped read tended to has lower MIC of anti-TB drugs than those with higher proportion. These results emphasize the high applicability of WGS for determination of DR-TB and the association of particular mutations with MIC levels.

scholarly journals Drug-sensitivity test and analysis of drug-resistant mutations in Mycobacterium tuberculosis isolates from Kashgar, China

2021 ◽  
Vol 19 ◽  
pp. 205873922110414
Author(s):  
Zhongchen Ma ◽  
Tianhao Sun ◽  
Xinyu Bai ◽  
Xiang Ji ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Dna Sequencing ◽  
High Sensitivity ◽  
Drug Susceptibility ◽  
Resistance Rate ◽  
Clinical Isolates ◽  
Multi Drug Resistance ◽  
Drug Resistant ◽  
Resistance Rates

Introduction In recent years, drug-resistant Mycobacterium tuberculosis strains have gradually become widespread. Most drug resistance is related to specific mutations. We investigated M. tuberculosis drug resistance in the Kashgar area, China. Methods The drug-susceptibility test was conducted to clinical isolates of M. tuberculosis. Genomic-sequencing technology was used for the drug-resistant strains and the significance of DNA sequencing as a rapid aid for drug-resistance detection and the diagnosis method was evaluated. Results The resistance rates of clinical isolates to rifampicin (RFP), isoniazid (INH), streptomycin (SM), ethambutol (EMB), and ofloxacin (OFX) were, respectively, 4.4%, 12.3%, 8.8%, 2.6%, and 3.5%. The single- and multi-drug resistance rates were, respectively, 80.0% and 20.0%. The resistance genes RopB, katG, InhA, RpsL, rrs, gyrA, and embB displayed codon mutations, while InhA was mutated in its promoter region. Kappa scores, evaluating the consistency between DNA sequencing and the resistance ratio methods for the detection of isolates’ resistance to RFP, INH, SM, OFX, and EMB, were 1, 0.955, 0.721, 0.796, and 1, respectively. Conclusion The resistance rate of INH and SM is relatively high in the Kashgar area. Detection of mutations in RopB, katG, InhA, RpsL, rrs, gyrA, and embB by DNA sequencing can predict drug resistance of M. tuberculosis strains with high sensitivity and specificity, and can be used for diagnosis.

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