Integrated analysis of ethionamide resistance loci in Mycobacterium tuberculosis clinical isolates

Silva, Duanne Alves da; Ferreira, Nicole Victor; Rêgo, Amanda M.; Barbosa, Pamela Chrystina Pinto; Machado, Rodrigo Fernandes; Pimentel, A. Fonseca; Reis, Lusiano Motta dos; Pina, Lucindo Cardoso de; Redner, Paulo; Caldas, Paulo César de Souza; Montes, Fátima Cristina Onofre Fandinho; Borga, Liamar; Leite, Suzanne Pereira; Rocha, Jorge Luiz da; Bastos, Leonardo Soares; Ramos, Jesus Pais; Degrave, Wim; Antunes, L. Caetano M.; Galvão, Teca Calcagno

doi:10.1016/j.tube.2018.08.010

Cited by 10 publications

(12 citation statements)

References 64 publications

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“…The Y50C mutation has been found in three ETH R clinical isolates [29] and Y50 is conserved in other BVMOs for which threedimensional structures are available (CHMO, PAMO, OTEMO, and STMO; [18]). It is part of the EthA region that concentrates a large number of mutations in ETH R isolates and which displays 67% similarity to an OTEMO stretch rich in FADH2 and NADP binding amino acids [18]. Also, mutation of the equivalent amino acid in OTEMO, Y53, to phenylalanine, reduces catalysis to 30% [20].…”

Section: Free Energy Changes For Y50c and T453i Etha Mutantsmentioning

confidence: 99%

“…OTEMO domains are as in [20]. An alignment between PAMO, CHMO, STMO, OTEMO, and EthA [18] was used to infer EthA domains and EthA and OTEMO mobile functional regions. Figure 2 shows the 3D alignment between the EthA model and 3UOZ.…”

Section: Comparative Modelingmentioning

confidence: 99%

“…The amino acids contributing to FADH2 and NADP binding in OTEMO are mostly conserved in EthA (Figure 2b,c), but there are two important differences. First, in OTEMO, T442 and C444-V446 hold catalytic R337 near the FADH2 isoalloxazine ring; this stretch of amino acids is missing in EthA, and, is not conserved in other BVMOs [18]. Second, the catalytic arginine, R292, is at a different position in EthA, possibly as a result of the absence of the above-mentioned amino acids.…”

Section: Comparative Modelingmentioning

confidence: 99%

“…Mutations Y50C and T453I are likely to cause resistance as they were identified in ETH R clinical isolates. Y50 lines the EthA binding pocket for FADH2 and NADP [18], and mutation of the equivalent tyrosine in OTEMO reduces catalysis [20]. T453 is in the control loop region, whose movement is essential for catalysis.…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates

Souza¹,

Antunes²,

Santos³

et al. 2020

Preprint

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Mutation in the ethionamide (ETH) activating enzyme, EthA, is the main factor determining resistance to this drug, used to treat TB patients infected with MDR and XDR Mycobacterium tuberculosis isolates. Many mutations in EthA of ETH resistant (ETH-R) isolates have been described but their roles in resistance remain uncharacterized, partly because structural studies on the enzyme are lacking. Thus, we took a two-tier approach to evaluate two mutations (Y50C and T453I) found in ETH-R clinical isolates. First, we used a combination of comparative modeling, molecular docking, and molecular dynamics to build an EthA model in complex with ETH that has hallmark features of structurally characterized homologs. Second, we used free energy computational calculations for the reliable prediction of relative free energies between the wild type and mutant enzymes. The ΔΔG values for Y50C and T453I mutant enzymes in complex with FADH2-NADP-ETH were 3.34 (+/−0.55) and 8.11 (+/−0.51) kcal/mol, respectively, compared to the wild type complex. The positive ΔΔG values indicate that the wild type complex is more stable than the mutants, with the T453I complex being the least stable. These are the first results shedding light on the molecular basis of ETH resistance, namely reduced complex stability of mutant EthA.

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Section: Free Energy Changes For Y50c and T453i Etha Mutantsmentioning

confidence: 99%

Section: Comparative Modelingmentioning

confidence: 99%

Section: Comparative Modelingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insights into the Mechanism of Ethionamide Resistance in Mycobacterium tuberculosis through an in silico Structural Evaluation of EthA and Mutants Identified in Clinical Isolates

Souza¹,

Antunes²,

Santos³

et al. 2020

Preprint

Self Cite

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“…29 Ethionamide resistance in Mtb occurs mainly by ethA mutations, deletion or mutation in msha coding for glycosyltransferase involved in mycothiol biosynthesis, mutations in ndh which codes for a type II NADH dehydrogenase, or mutations in inhA and/or its promoter region (c-15t). [30][31][32][33][34] Rare mutations in ethR relative to thioamides resistance have also been described. 32,35,36 Mutation in the intergenic region of ethA-ethR (t-11c), in combination with an inhA promoter mutation was described as leading to a high level of resistance.…”

Section: Ethr As a Validated Target To Boost The Bioactivation Of Ethionamidementioning

confidence: 99%

Recent advances in the design of inhibitors of mycobacterial transcriptional regulators to boost thioamides anti-tubercular activity and circumvent acquired-resistance

Willand

Flipo

Villemagne

et al. 2019

Annual Reports in Medicinal Chemistry

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With more than 1.6 million deaths per year, tuberculosis (TB) is today the major cause of mortality resulting from a bacterial infection. The principal obstacles to the global control of this infectious disease include the difficulties to detect and cure a sufficient number of cases to interrupt transmission. In addition, multidrug-resistant-TB (MDR-TB) has emerged as a major concern worldwide. Therapeutic solutions to stem this scourge are based on a 2 to 4 year treatment regimen of less effective second-line drug cocktails, often associated with serious side effects, which reduces patients compliance and thus leads to high rates of recurrence and mortality. In parallel to the search for new targets and new class of antibiotics, the development of strategies to improve the efficacy of drugs already used in the clinic have been proposed. One of these strategies takes advantage of the fact that many first-line and second-line anti-tubercular drugs are pro-drugs. Indeed, they need to be bioactivated by drug-specific mycobacterial enzymes in order to develop their anti-bacterial activity. Thioamides (ethionamide or prothionamide) are among the most frequently used drugs for the treatment of drug-resistant tuberculosis. Bioactivation of ethionamide occurs through the catalysis of a flavin-dependent Baeyer-Villiger monooxygenase called EthA. The resulting NAD-adduct inhibits InhA, an enoyl-ACP reductase of the type II fatty acid synthase (FAS-II) system, involved in cell-wall synthesis. The transcriptional repressor EthR, in turn, tightly controls the expression of ethA. A new therapeutic concept emerged from this observation and the development of EthR inhibitors was proposed as a solution to improve ethioanmide activity. In this chapter, we outline the most recent efforts of different research groups, using modern drug discovery strategies that led to the design, discovery and optimization of the first compounds able to inhibit EthR and boost the bioactivation of ETH in vitro and in vivo. We finally discuss the limitations of this approach and the breakthroughs in the identification of new chemical series and alternative bioactivation pathways that paves the way for the clinical development of a combination allowing thioamides to return fully active against all sensitive or resistant clinical isolates.

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Advancing against drug-resistant tuberculosis: an extensive review, novel strategies and patent landscape

Patel,

Nandpal

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Integrated analysis of ethionamide resistance loci in Mycobacterium tuberculosis clinical isolates

Cited by 10 publications

References 64 publications

Insights into the Mechanism of Ethionamide Resistance in <em>Mycobacterium tuberculosis</em> through an <em>in silico</em> Structural Evaluation of EthA and Mutants Identified in Clinical Isolates

Insights into the Mechanism of Ethionamide Resistance in <em>Mycobacterium tuberculosis</em> through an <em>in silico</em> Structural Evaluation of EthA and Mutants Identified in Clinical Isolates

Recent advances in the design of inhibitors of mycobacterial transcriptional regulators to boost thioamides anti-tubercular activity and circumvent acquired-resistance

Advancing against drug-resistant tuberculosis: an extensive review, novel strategies and patent landscape

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