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Frequency of Codon 306 Mutations in embB Gene of Mycobacterium tuberculosis Resistant to Ethambutol: A Systematic Review and Meta‑Analysis
Abstract
Background: Ethambutol (EMB) resistance is a major concern in patients with tuberculosis (TB). The aim of this study was to determine the frequency rate of mutations in the embB306 gene of Mycobacterium tuberculosis (M. tuberculosis) resistant to EMB, based on a systematic review and meta‑analysis.
Methods: Thirty‑seven original articles (1997–2015) that have been published in valid databases were considered for this research. The articles were systematically reviewed for the prevalence and rate of mutations in embB306 in EMB‑resistant M. tuberculosis. Data were analyzed using meta‑analysis and random effects models (CI 95%, P < 0.10).
Results: With a 6,931 sample size in 37 original articles, the lowest rate was related to EMB resistance that was observed in 2014 with 0.05 (95% CI: 0.04–0.07) and the highest prevalence rate was 0.84 (95% CI: 0.68–1.01), observed in 1997. Lowest and highest prevalence rates of embB306 gene mutation in M. tuberculosis were 0.03 (95% CI: 0.01–0.07) in 2014 and 0.78 (95% CI: 0.71–1.84) in 2005, in the USA, respectively.
Conclusions: The present study revealed the prevalence and association of mutations in the embB306 gene of M. tuberculosis with resistance to EMB. Detecting EMB‑resistant M. tuberculosis can help in controlling and correcting the administration of drugs for patients with TB.
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Zaman K. Tuberculosis: A global health problem. J Health Popul
Nutr 2010;28:111‑3.
Ramazanzadeh R, Roshani D, Shakib P, Rouhi S. Prevalence and
occurrence rate of Mycobacterium tuberculosis Haarlem family
multi‑drug resistant in the worldwide population: A systematic
review and meta‑analysis. J Res Med Sci 2015;20:78‑88.
Leibert E, Rom WN. New drugs and regimens for treatment of
TB. Expert Rev Anti Infect Ther 2010;8:801‑13.
Chhabra N, Aseri ML, Dixit R, Gaur S. Pharmacotherapy for multidrug resistant tuberculosis. J Pharmacol Pharmacother
;3:98‑104.
Fair RJ, Tor Y. Antibiotics and bacterial resistance in the
st century. Perspect Medicin Chem 2014;6:25‑64.
Smith T, Wolff KA, Nguyen L. Molecular biology of drug
resistance in Mycobacterium tuberculosis. Curr Top Microbiol
Immunol 2013;374:53‑80.
Mohammadi B, Mohajeri P, Rouhi S, Ramazanzadeh R. The
relationship between embB306 and embB406 mutations and
ethambutol resistant in Mycobacterium tuberculosis isolated
from patients in west of Iran. Med J Islam Repub Iran
;32:117.
Adebayo OA, Adesanoye OA, Abolaji OA, Kehinde AO,
Adaramoye OA. First‑line antituberculosis drugs disrupt
endocrine balance and induce ovarian and uterine oxidative
stress in rats. J Basic Clin Physiol Pharmacol 2018;29:131‑40.
Angala SK, Belardinelli JM, Huc‑Claustre E, Wheat WH,
Jackson M. The cell envelope glycoconjugates of Mycobacterium
tuberculosis. Crit Rev Biochem Mol Biol 2014;49:361‑99.
Alderwick LJ, Harrison J, Lloyd GS, Birch HL. The
Mycobacterial cell wall—peptidoglycan and arabinogalactan.
Cold Spring Harb Perspect Med 2015;5:a021113.
Brossier F, Sougakoff W, Bernard C, Petrou M, Adeyema K,
Pham A, et al. Molecular analysis of the embCAB locus and
embR gene involved in ethambutol resistance in clinical isolates
of Mycobacterium tuberculosis in France. Antimicrob Agents
Chemother 2015;59:4800‑8.
Dookie N, Rambaran S, Padayatchi N, Mahomed S, Naidoo K.
Evolution of drug resistance in Mycobacterium tuberculosis:
A review on the molecular determinants of resistance and
implications for personalized care. J Antimicrob Chemother
;73:1138‑51.
Zhao L, Sun Q, Liu H, Wu X, Xiao T, Zhao X, et al. Analysis
of embCAB mutations associated with ethambutol resistance in
multidrug‑resistant Mycobacterium tuberculosis isolates from
China. Antimicrob Agents Chemother 2015;59:2045‑50.
Naser Esfahani B, Zarkesh FS, Rezaei Yazdi H, Radaee T.
Detection of embB gene mutations in EMB‑resistant
Mycobacterium tuberculosis isolates from Isfahan province by
PCR‑SSCP and direct sequencing. Jundishapur J Microbiol
;9:e39594.
Al‑Saeedi M, Al‑Hajoj S. Diversity and evolution of drug
resistance mechanisms in Mycobacterium tuberculosis. Infect
Drug Resist 2017;10:333‑42.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC,
Ioannidis JPA, et al. The PRISMA statement for reporting
systematic reviews and meta‑analyses of studies that evaluate
health care interventions: Explanation and elaboration. PLoS
Med 2009;6:339.
Shi D, Li L, Zhao Y, Jia Q, Li H, Coulter C, et al. Characteristics
of embB mutations in multidrug‑resistant Mycobacterium
tuberculosis isolates in Henan, China. J Antimicrob Chemother
;66:2240‑7.
Lee AS, Othman SNK, Ho YM, Wong SY. Novel mutations
within the embB gene in ethambutol‑susceptible clinical isolates
of Mycobacterium tuberculosis. Antimicrob Agents Chemother
;48:4447‑9.
Ahmad S, Mokaddas E, Jaber AA. Rapid detection of
ethambutol‑resistant Mycobacterium tuberculosis strains by
PCR‑RFLP targeting embB codons 306 and 497 and iniA codon
mutations. Mol Cell Probes 2004;18:299‑306.
Shi R, Zhang J, Otomo K, Zhang G, Sugawara I. Lack of
correlation between embB mutation and ethambutol MIC in Mycobacterium tuberculosis clinical isolates from China.
Antimicrob Agents Chemother 2007;51:4515‑7.
Rinder H, Mieskes KT, Tortoli E, Richter E, Casal M,
Vaquero M, et al. Detection of embB codon 306 mutations in
ethambutol resistant Mycobacterium tuberculosis directly from
sputum samples: A low‑cost, rapid approach. Mol Cell Probes
;15:37‑42.
Hazbon MH, del Valle MB, Guerrero MI, Varma‑Basil M,
Filliol I, Cavatore M, et al. Role of embB codon 306 mutations
in Mycobacterium tuberculosis revisited: A novel association with
broad drug resistance and IS6110 clustering rather than ethambutol
resistance. Antimicrob Agents Chemother 2005;49:3794‑802.
Guerrero E, Lemus D, Yzquierdo S, Vilchez G, Munoz M,
Montoro E, et al. Association between embB mutations and
ethambutol resistance in Mycobacterium tuberculosis isolates
from Cuba and the Dominican Republic: Reproducible patterns
and problems. Rev Argent Microbiol 2013;45:21‑6.
Plinke C, Rüsch‑Gerdes S, Niemann S. Significance of mutations
in embB codon 306 for prediction of ethambutol resistance in
clinical Mycobacterium tuberculosis isolates. Antimicrob Agents
Chemother 2006;50:1900‑2.
Bakula Z, Napiorkowska A, Bielecki J, Augustynowicz‑Kopec E,
Zwolska Z, Jagielski T. Mutations in the embB gene and their
association with ethambutol resistance in multidrug‑resistant
Mycobacterium tuberculosis clinical isolates from Poland.
Biomed Res Int 2013;2013:167954.
Zhang Z, Wang Y, Pang Y, Kam KM. Ethambutol resistance
as determined by broth dilution method correlates better than
sequencing results with embB mutations in multidrug‑resistant
Mycobacterium tuberculosis isolates. J Clin Microbiol
;52:638‑41.
Starks AM, Gumusboga A, Plikaytis BB, Shinnick TM,
Posey JE. Mutations at embB Codon 306 are an important
molecular indicator of ethambutol resistance in Mycobacterium
tuberculosis. Antimicrob Agents Chemother 2009;53:1061‑6.
Wu XQ, Liang JQ, Zhang JX, Lu Y, Li HM, Zhang GY, et al.
Detection and evaluation of the mutations of embB gene in
ethambutol‑susceptible and resistant Mycobacterium tuberculosis
isolates from China. Chinese Med J 2005;118:1739‑41.
Tracevska T, Jansone I, Nodieva A, Marga O, Skenders G,
Baumanis V. Characterisation of rpsL, rrs and embB mutations
associated with streptomycin and ethambutol resistance in
Mycobacterium tuberculosis. Res Microbiol 2004;155:830‑34.
Sreevatsan S, Stockbauer KE, Pan X, Kreiswirth BN,
Moghazeh SL, Jacobs W, et al. Ethambutol resistance in
Mycobacterium tuberculosis: Critical role of embB mutations.
Antimicrob Agents Chemother 1997;41:1677‑81.
Kim SH, Park M, Woo H, Tharmalingam N, Lee G, Rhee KJ,
et al. Inhibitory effects of anthocyanins on secretion of
Helicobacter pylori CagA and VacA toxins. Int J Med Sci
;9:838‑42.
Moure R, Espanol M, Tudo G, Vicente E, Coll P,
Gonzalez‑Martin J, et al. Characterization of the embB gene in
Mycobacterium tuberculosis isolates from Barcelona and rapid
detection of main mutations related to ethambutol resistance
using a low‑density DNA array‑authors’ response. J Antimicrob
Chemother 2014;69:2299‑300.
Li W, Xue X, Chu Y, Qiu Y, Song J, Zheng J. Correlation
between ethambutol‑resistance and embB gene mutation in
Mycobacterium tuberculosis. Wei Sheng Yan Jiu 2010;39:506‑8.
Lee H, Myoung HJ, Bang HE, Bai GH, Kim SJ, Kim JD, et al.
Mutations in the embB locus among Korean clinical isolates of
Mycobacterium tuberculosis resistant to ethambutol. Yonsei Med
J 2002;43:59‑64.
Afanas’ev MV, Borovskaia AD, Il’ina EN, Smirnova TG,
Larionova EE, Kuz’min AV, et al. Detection of mutations
in codon 306 of the embB gene for molecular genetic
characterization of clinical Mycobacterium tuberculosis strains.
Probl Tuberk Bolezn Legk 2009;2009:48‑53.
Ramaswamy SV, Amin AG, Göksel S, Stager CE, Dou SJ,
El Sahly H, et al. Molecular genetic analysis of nucleotide
polymorphisms associated with ethambutol resistance in human
isolates of Mycobacterium tuberculosis. Antimicrob Agents
Chemother 2000;44:326‑36.
Parsons LM, Salfinger M, Clobridge A, Dormandy J,
Mirabello L, Polletta VL, et al. Phenotypic and molecular
characterization of Mycobacterium tuberculosis isolates resistant
to both isoniazid and ethambutol. Antimicrob Agents Chemother
;49:2218‑25.
Hillemann D, Rüsch‑Gerdes S, Richter E. Feasibility
of the GenoType MTBDRsl assay for fluoroquinolone,
amikacin‑capreomycin, and ethambutol resistance testing of
Mycobacterium tuberculosis strains and clinical specimens.
J Clin Microbiol 2009;47:1767‑72.
Van Rie A, Warren R, Mashanga I, Jordaan AM, Van Der
Spuy G, Richardson M, et al. Analysis of a limited number
of gene codons can predict the majority of drug resistance of
Mycobacterium tuberculosis in a high incidence area. J Clin
Microbiol 2001;39:636‑41.
Hu Y, Hoffner S, Jiang W, Wang W, Xu B. Genetic
characterisation of drug‑resistant Mycobacterium tuberculosis
in rural China: A population‑based study. Int J Tuberc Lung Dis
;14:210‑16.
Brossier F, Veziris N, Aubry A, Jarlier V, Sougakoff W. Detection
by MTBDRsl test of complex resistance mechanisms to
second‑line drugs and ethambutol in multidrug‑resistant strains of
Mycobacterium tuberculosis. J Clin Microbiol 2010;48:1683‑9.
Moure R, Español M, Tudó G, Vicente E, Coll P, Gonzalez‑Martin J,
et al. Characterization of the embB gene in Mycobacterium
tuberculosis isolates from Barcelona and rapid detection of main
mutations related to ethambutol resistance using a low‑density
DNA array. J Antimicrob Chemother 2014;69:947‑54.
Johnson R, Jordaan A, Pretorius L, Engelke E, Van Der Spuy G,
Kewley C, et al. Ethambutol resistance testing by mutation
detection. Int J Tuberc Lung Dis 2006;10:68‑73.
Feuerriegel S, Oberhauser B, George AG, Dafae F, Richter E,
Rüsch‑Gerdes S, et al. Sequence analysis for detection of
first‑line drug resistance in Mycobacterium tuberculosis strains
from a high‑incidence setting. BMC Microbiol 2012;12:90.
Luo T, Zhao M, Li X, Xu P, Gui X, Pickerill S, et al. Selection
of mutations to detect multidrug‑resistant Mycobacterium
tuberculosis strains in Shanghai, China. Antimicrob Agents
Chemother 2010;54:1075‑81.
Xu Y, Jia H, Huang H, Sun Z, Zhang Z. Mutations found
in embCAB, embR, and ubiA genes of ethambutol‑sensitive
and‑resistant Mycobacterium tuberculosis clinical isolates from
China. Biomed Res Int 2015;2015:951706.
Zhao LL, Sun Q, Liu HC, Wu XC, Xiao TY, Zhao XQ, et al.
Analysis of embCAB mutations associated with ethambutol
resistance in multidrug‑resistant Mycobacterium tuberculosis
isolates from China. Antimicrob Agents Chemother
;59:2045‑50.
Cuevas‑Córdoba B, Juárez‑Eusebio DM, Almaraz‑Velasco R,
Muñiz‑Salazar R, Laniado‑Laborin R, Zenteno‑Cuevas R.
Mutation at embB codon 306, a potential marker for the
identification of multidrug resistance associated with ethambutol
in Mycobacterium tuberculosis. Antimicrob Agents Chemother
;59:5455‑62.
Perdigao J, Macedo R, Ribeiro A, Brum L, Portugal I. Genetic
characterisation of the ethambutol resistance‑determining region
in Mycobacterium tuberculosis: Prevalence and significance of
embB306 mutations. Int J Antimicrobial Agents 2009;33:334‑8.
Mokrousov I, Narvskaya O, Limeschenko E, Otten T,
Vyshnevskiy B. Detection of ethambutol‑resistant Mycobacterium
tuberculosis strains by multiplex allele‑specific PCR assay
targeting embB306 mutations. J Clin Microbiol 2002;40:1617‑20.
Shen X, Shen GM, Wu J, Gui XH, Li X, Mei J, et al. Association
between embB codon 306 mutations and drug resistance in
Mycobacterium tuberculosis. Antimicrob Agents Chemother
;51:2618‑20.
Lin H, Liu J, Chen L, Jing KH, Shen J, Zhan J, et al. Molecular
characterization of embB306 gene in Mycobacterium tuberculosis
isolates from tuberculosis patients in Chongqing municipality.
Zhonghua Yu Fang Yi Xue Za Zhi 2009;43:223‑6.
Wang Y, Zhang WH, Zhao JR, Luo M, Zhang ZX, Bai YJ, et al.
Detect embB306 gene mutation associated with EMB resistance
of M. tuberculosis by TDI‑FP technology. Chinese J Lab Diagn
;27:179‑82.
Margaryan H, Rüsch‑Gerdes S, Hayrapetyan A, Mirzoyan A.
Ethambutol‑resistance testing by mutation detection using
MTBDRsl. Int J Mycobacteriol 2016;5:S50.
Ramazanzadeh R, Mohammadi B, Mohajeri P. Mutations
in embB gene associated with resistance to ethambutol in
Mycobacterium tuberculosis strains isolated from TB patients in
the west of Iran (2014–15). Int J Mycobacteriol 2016;5:S140.
Munir S, Mahmood N, Shahid S, Khan MI. Molecular
detection of isoniazid, rifampin and ethambutol resistance
to M. tuberculosis and M. bovis in multidrug resistant
tuberculosis (MDR‑TB) patients in Pakistan. Microb Pathog
;110:262‑74.
Goude R, Amin AG, Chatterjee D, Parish T. The
arabinosyltransferase EmbC is inhibited by ethambutol in
Mycobacterium tuberculosis. Antimicrob Agents Chemother
;53:4138‑46.
Operario DJ, Koeppel AF, Turner SD, Bao Y, Pholwat S,
Banu S, et al. Prevalence and extent of heteroresistance by next
generation sequencing of multidrug‑resistant tuberculosis. PLoS
One 2017;12:e0181284.
Khosravi A, Sirous M, Abdi M, Ahmadkhosravi N.
Characterization of the most common embCAB gene mutations
associated with ethambutol resistance in Mycobacterium
tuberculosis isolates from Iran. Infect Drug Resist
;12:579‑84.
Babamahmoodi F, Alikhani A, Yazdani Charati J, Ghovvati A,
Ahangarkani F, Delavarian L, Babamahmoodi A. Clinical
epidemiology and paraclinical findings in tuberculosis patients in
north of Iran. Biomed Res Int 2015;2015:1‑5.
Rezai MS, Ahangarkani F, Sadeghi R, Mahdavi MR. Evaluation
of children with complication of BCG vaccination in north of
Iran. Int J Pediatr 2017;5:4479‑88.
Jabbar A, Phelan JE, de Sessions PF, Khan TA, Rahman H,
Khan SN, et al. Whole genome sequencing of drug resistant
Mycobacterium tuberculosis isolates from a high burden
tuberculosis region of North West Pakistan. Sci Rep
;9:14996.