Role of embCAB gene mutations in ethambutol resistance in Mycobacterium tuberculosis isolates from India

Jadaun, G. P. S.; Das, Ram; Upadhyay, Prashant; Chauhan, D. S.; Sharma, V. D.; Katoch, Vishwa Mohan

doi:10.1016/j.ijantimicag.2008.10.017

Cited by 20 publications

(11 citation statements)

References 14 publications

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“…EmbB mutations are often associated with high-level resistance in clinical isolates, but mutations in codon 306 are not sufficient on their own to generate high-level resistance (23), so presumably there are secondary mutations (which may be dependent on strains already having EmbB mutations). In support of this, a recent study showed that a combination of mutations in EmbB codon 306 and EmbC codon 270 resulted in higher levels of resistance (11). In this light, it is interesting that construction of an isogenic strain carrying EmbC(T270I) alone demonstrated that this mutation played no role in me- Since AG is also essential, forming part of the structural integrity of the cell wall, this would lead to a severe growth defect.…”

Section: Discussionmentioning

confidence: 97%

The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in Mycobacterium tuberculosis

Goude

Amin

Chatterjee

et al. 2009

Antimicrob Agents Chemother

119

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Ethambutol (EMB) is an antimycobacterial drug used extensively for the treatment of tuberculosis caused by Mycobacterium tuberculosis. EMB targets the biosynthesis of the cell wall, inhibiting the synthesis of both arabinogalactan and lipoarabinomannan (LAM), and is assumed to act via inhibition of three arabinosyltransferases: EmbA, EmbB, and EmbC. EmbA and EmbB are required for the synthesis of arabinogalactan, and at least one enzyme (M. tuberculosis EmbA [EmbA Mt ]) is essential in M. tuberculosis. EmbC Mt is also essential for the viability of M. tuberculosis but is involved in the synthesis of LAM. We show that mutations in EmbC Mt that reduce its arabinosyltransferase activity result in increased sensitivity to EMB and the production of smaller LAM species in M. tuberculosis. Overexpression of EmbC Mt was not tolerated in M. tuberculosis, but overexpression of Mycobacterium smegmatis EmbC (EmbC Ms ) led to EMB resistance and the production of larger LAM species in M. tuberculosis. Treatment of wild-type M. tuberculosis strains with EMB led to inhibition of LAM synthesis, resulting in the production of smaller species of LAM. In contrast, no change in LAM production was seen in EMB-resistant strains. Overexpression of EmbB Ms in M. tuberculosis also resulted in EMB resistance, but at a lower level than that caused by EmbC Ms . Overexpression of EmbA Mt in M. tuberculosis had no effect on EMB resistance. Thus, there is a direct correlation between EmbC activity and EMB resistance, as well as between EmbC activity and the size of the LAM species produced, confirming that EmbC is one of the cellular targets of EMB action.Tuberculosis (TB), one of the oldest diseases known to humans, remains a major public health threat. It is estimated that one-third of the world's population are infected with the causative agent, Mycobacterium tuberculosis. The scale of the problem is increasing, and the disease is becoming deadlier as it intersects with the spread of human immunodeficiency virus. The emergence of multidrug-resistant strains establishes the urgent need to fully understand the mechanisms of drug resistance. Ethambutol (EMB) is a bacteriostatic, antimycobacterial drug first described in 1961 (31) and has been prescribed for TB treatment since 1966. EMB is used worldwide for TB therapy in combination with isoniazid, pyrazinamide, and rifampin (rifampicin). It is also effective in the treatment of opportunistic mycobacterial infections of patients with human immunodeficiency virus. Unfortunately, resistance to EMB has been reported in as many as 4% of clinical isolates of M. tuberculosis and is prevalent among multidrug-resistant strains (5).The effects of EMB are highly pleiotropic, and over the past 40 years, many efforts have been made to understand its intracellular target(s). Kilburn and Greenberg (12) were the first to indicate that EMB treatment of Mycobacterium smegmatis caused rapid bacterial declumping, suggesting cell wall changes. It was subsequently demonstrated that EMB inhibited the transfer of m...

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Section: Discussionmentioning

confidence: 97%

The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in Mycobacterium tuberculosis

Goude

Amin

Chatterjee

et al. 2009

Antimicrob Agents Chemother

119

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“…Some reports suggested that the isolates with mutation combinations presented higher-level EMB resistance (14,25,26). Nevertheless, the relevance of these mutations in EMB resistance was unclear and deserved further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…All sequence data were aligned with the corresponding sequences of published H37Rv data (GenBank accession number NC_000962) using BioEdit software version 7.05.3. All the mutations found were compared with those contained in the TB Drug Resistance Mutation Database (www.tbdreamdb.com) (24) and previous publications (3,5,15,25,26). Novel mutations were defined as mutations not included in the database and publications.…”

Section: Mycobacterium Tuberculosis Isolatesmentioning

confidence: 99%

Analysis of embCAB Mutations Associated with Ethambutol Resistance in Multidrug-Resistant Mycobacterium tuberculosis Isolates from China

Zhao

Sun

Liu

et al. 2015

Antimicrob Agents Chemother

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e Ethambutol (EMB) plays a pivotal role in the chemotherapy of drug-resistant tuberculosis (TB), including multidrug-resistant tuberculosis (MDR-TB). Resistance to EMB is considered to be caused by mutations in the embCAB operon (embC, embA, and embB). In this study, we analyzed the embCAB mutations among 139 MDR-TB isolates from China and found a possible association between embCAB operon mutation and EMB resistance. Our data indicate that 56.8% of MDR-TB isolates are resistant to EMB, and 82.2% of EMB-resistant isolates belong to the Beijing family. Overall, 110 (79.1%) MDR-TB isolates had at least one mutation in the embCAB operon. The majority of mutations were present in the embB gene and the embA upstream region, which also displayed significant correlations with EMB resistance. The most common mutations occurred at codon 306 in embB (embB306), followed by embB406, embA(؊16), and embB497. Mutations at embB306 were associated with EMB resistance. DNA sequencing of embB306 -497 was the best strategy for detecting EMB resistance, with 89.9% sensitivity, 58.3% specificity, and 76.3% accuracy. Additionally, embB306 had limited value as a candidate predictor for EMB resistance among MDR-TB infections in China.M ultidrug-resistant tuberculosis (MDR-TB) is attributed to an estimated 3.7% new cases and 20.2% previously treated cases of TB annually worldwide and is becoming a major threat to global public health (1). In China, the significantly high prevalence (5.7% new cases and 25.6% previously treated cases) of MDR-TB makes TB control especially challenging (2). Ethambutol (EMB) is an important first-line anti-TB drug routinely recommended for therapy of drug-resistant TB, including MDR-TB. Disturbingly, in some regions of China, substantial proportions (51.3% to 66.7%) of MDR-TB isolates demonstrated EMB resistance (3-5). Development of new rapid and reliable molecular methods for detecting drug resistance is essential to optimize treatment regimens, prevent treatment failure, and thus reduce the further spread of drug-resistant isolates. However, these molecular assays require precise knowledge of the genetic mutations associated with drug resistance. Prior studies indicated that the characteristics of resistance-associated mutations vary in different regions (6, 7). EMB acts against TB by inhibiting membrane-associated arabinosyl transferases encoded by the embCAB operon (including embC, embA, and embB), which are involved in the synthesis of cell wall arabinogalactan (8,9). Approximately 50% to 70% of EMB-resistant TB isolates harbor mutations in a relatively short fragment (codons 306 -497) in embB genes, with mutations occurring most frequently at codon 306 in embB (embB306), embB406, and embB497 (5,8,(10)(11)(12)(13). Sequence analysis of this fragment has been a tool for the rapid detection of EMB resistance. However, approximately one third of EMB-resistant isolates do not carry changes in this region and therefore are not detectable by using DNA sequencing (12,14). Although other mutations in the embCAB...

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“…Their finding that the Thr270Ile change on its own plays no role in EMB resistance is of particular importance (9). Clinical studies had found this mutation in numerous EMB-resistant but also some EMB-sensitive isolates (13,15,16,(19)(20)(21). However, given that this mutation usually coincided with additional mutations in embCAB, its relevance for EMB resistance remained unclear (15).…”

Section: Thr270ile In Embc (Rv3793) Is Not a Marker For Ethambutol Rementioning

confidence: 99%

Thr270Ile in embC ( Rv3793 ) Is Not a Marker for Ethambutol Resistance in the Mycobacterium tuberculosis Complex

Köser

Summers

Archer

2011

Antimicrob Agents Chemother

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Role of embCAB gene mutations in ethambutol resistance in Mycobacterium tuberculosis isolates from India

Cited by 20 publications

References 14 publications

The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in Mycobacterium tuberculosis

The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in Mycobacterium tuberculosis

Analysis of embCAB Mutations Associated with Ethambutol Resistance in Multidrug-Resistant Mycobacterium tuberculosis Isolates from China

Thr270Ile in embC ( Rv3793 ) Is Not a Marker for Ethambutol Resistance in the Mycobacterium tuberculosis Complex

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