Contribution of
 dfrA
 and
 inhA
 Mutations to the Detection of Isoniazid-Resistant
 Mycobacterium tuberculosis
 Isolates

Ho, Yu Min; Sun, Yong-Jiang; Wong, Serre-Yu; Lee, Ann S. G.

doi:10.1128/aac.00433-09

Cited by 27 publications

(13 citation statements)

References 27 publications

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“…Mutations in a number of other genes have been identified in INH-resistant M.tuberculosis strains (19) . However, approximately 22-29% of INH-resistant strains do not possess mutations in genes known to affect INHresistance (20) (21) , indicating that there may be unexplored mechanisms that influence INH efficacy in M.tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

Examining the Basis of Isoniazid Tolerance in Nonreplicating Mycobacterium Tuberculosis Using Transcriptional Profiling

et al. 2010

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Background: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. Results: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. Conclusion: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance.

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Section: Introductionmentioning

confidence: 99%

Examining the Basis of Isoniazid Tolerance in Nonreplicating Mycobacterium Tuberculosis Using Transcriptional Profiling

et al. 2010

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“…A higher prevalence of mutations in katG (associated with a high level of INH resistance) than in the inhA/inhA promoter region (associated with a low level of INH resistance and coresistance to ETH) accounts for the fact that cross-resistance to the two drugs is not systematic in clinical strains, making the use of ETH in cases of INH resistance possible (30 (15). Few systematic studies on the distribution of nucleotide changes affecting the above-mentioned genes and focused primarily on a limited number of genes have been conducted (4,10,13,17,21,24).…”

mentioning

confidence: 99%

Molecular Investigation of Resistance to the Antituberculous Drug Ethionamide in Multidrug-Resistant Clinical Isolates of Mycobacterium tuberculosis

Brossier

Véziris

Truffot-Pernot

et al. 2011

Antimicrob Agents Chemother

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Ethionamide (ETH) needs to be activated by the mono-oxygenase EthA, which is regulated by EthR, in order to be active against Mycobacterium tuberculosis. The activated drug targets the enzyme InhA, which is involved in cell wall biosynthesis. Resistance to ETH has been reported to result from various mechanisms, including mutations altering EthA/EthR, InhA and its promoter, the NADH dehydrogenase encoded by ndh, and the MshA enzyme, involved in mycothiol biosynthesis. r isolates without a mutation in these three genes (9/47, 19%) had no mutation in ndh, and a single isolate had a mutation in mshA. Of the 16 ETH Sip isolates, 7 had a mutation in ethA, 8 had no detectable mutation, and 1 had a mutation in mshA. Finally, of the 24 ETH s isolates, 23 had no mutation in the studied genes and 1 displayed a yet unknown mutation in the inhA promoter. Globally, the mechanism of resistance to ETH remained unknown for 19% of the ETH r isolates, highlighting the complexity of the mechanisms of ETH resistance in M. tuberculosis.Ethionamide (ETH), a second-line antituberculous drug, is a structural thioamide analogue of isoniazid (INH), the cornerstone of front-line tuberculosis (TB) treatment. ETH is considered to be the most active antituberculous drug after aminoglycosides and fluoroquinolones and is a component of most of the drug regimens used for treating multidrug-resistant (MDR) TB (MDR-TB) or suspected MDR-TB (25, 32). To date, drug susceptibility testing (DST) for ETH relies mainly on phenotypic tests because the molecular mechanisms of ETH resistance are not fully understood. In vitro phenotypic investigation of ETH resistance is experimentally difficult and can yield discordant results according to the experimental method and resistance breakpoint values used, which still remain matters of debate (26). Therefore, a genotypic approach would be of great value to improve and hasten DST and the management of MDR-TB, as well as reduce the proportion of patients inadequately treated on the basis of erroneous DST results, consequently limiting the emergence of extensively drug-resistant tuberculosis among patients treated for MDR-TB.ETH and INH share the same molecular target, the NADHdependent enoyl-acyl carrier protein reductase InhA of the fatty acid biosynthesis type II system, which is involved in the synthesis of mycolic acids (2, 19). Consequently, cross-resistance to these two antibiotics can be observed in clinical isolates. However, though ETH is a structural analogue of INH, cross-resistance between ETH and INH does not occur systematically. Strains with low-level resistance to INH frequently display low-level ETH resistance, whereas high-level INH-resistant (INH r ) strains typically remain ETH susceptible (ETH s ) (6,7,21). This apparent paradox is due to the fact that INH and ETH are prodrugs that need to be activated by mycobacterial enzymes in order to exert their antimicrobial activity, with each drug being activated by a specific mechanism. INH is activated by the katG-encoded catalase-peroxidase (33), ...

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“…77 It was also recently suggested that mutations in dfrA play a role in resistance to isoniazid, 78 although other, more recent, studies have not corroborated this assertion. 79,80 Furthermore, mutations in thyA, which encodes thymidylate synthase, have been also suggested to confer resistance to trimethoprim/sulfamethoxazole. 81 Taking all this into consideration, and to better define the possible role of trimethoprim/sulfamethoxazole as a repositioned drug, adding to the anti-TB drug armamentarium, it will be Review 277 JAC necessary to further corroborate the few available studies that have reported activity of trimethoprim/sulfamethoxazole, or perhaps sulfamethoxazole alone, against a larger number of clinical isolates from different settings.…”

Section: Activity Of Trimethoprim/sulfamethoxazole Against Tbmentioning

confidence: 99%

Is repositioning of drugs a viable alternative in the treatment of tuberculosis?

Palomino

Martin

2012

Journal of Antimicrobial Chemotherapy

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Antimicrobial resistance is a serious problem because of the scarcity of new antibiotics effective against pathogens such as methicillin-resistant Staphylococcus aureus, β-lactamase-producing Gram-negative bacteria and multidrug-resistant Mycobacterium tuberculosis. Extensively drug resistance is particularly worrying in tuberculosis (TB), since the causative bacteria have become resistant to almost all available first- and second-line drugs and resistance is a threat to achieving control of the disease. Development of new drugs is a lengthy and costly endeavour. This is a particular problem for antibiotics, usage of which is likely to be of limited duration, and is even more true of antibiotics whose use is restricted to the treatment of a disease, such as TB, that is considered to be 'poverty related', and for which the return on the investment is seen as non-attractive. In spite of this, there is an emerging pipeline of new drugs under development that hopefully will bring new anti-TB drugs to the market in the near future. The strategy of drug repurposing, finding new uses for existing approved medicines, has seen unexpected success in other medical areas. More than one blockbuster drug has originated from this strategy. And in the field of TB, there have been several examples in recent years of this approach leading to the use of drugs for which there is undeniable evidence of efficacy in the treatment of the disease, the best example being the fluoroquinolones, which were not developed originally to treat TB. This article reviews some examples of repurposing of drugs in the treatment of TB, newer candidates for repurposing for which there is already preliminary evidence of activity and possible new options that merit further investigation.

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Contribution of dfrA and inhA Mutations to the Detection of Isoniazid-Resistant Mycobacterium tuberculosis Isolates

Cited by 27 publications

References 27 publications

Examining the Basis of Isoniazid Tolerance in Nonreplicating Mycobacterium Tuberculosis Using Transcriptional Profiling

Examining the Basis of Isoniazid Tolerance in Nonreplicating Mycobacterium Tuberculosis Using Transcriptional Profiling

Molecular Investigation of Resistance to the Antituberculous Drug Ethionamide in Multidrug-Resistant Clinical Isolates of Mycobacterium tuberculosis

Is repositioning of drugs a viable alternative in the treatment of tuberculosis?

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