Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2

Wohlkonig, A.; Remaut, Han; Moune, Martin; Tanina, Abdalkarim; Meyer, Franck; Desroses, Matthieu; Steyaert, Jan; Willand, Nicolas; Baulard, Alain R.; Wintjens, René

doi:10.1016/j.bbrc.2017.04.074

Cited by 10 publications

(9 citation statements)

References 31 publications

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“…To gain an understanding of how Rv0078 represses gene expression, we solved the crystal structure of Rv0078 to 1.85 Å by a single-wavelength anomalous dispersion method. As previously reported, Rv0078 forms dimers resembling other TetR-like proteins ( 13 , 14 ). Unlike the canonical TetR binding site, tetO , which is 15 bp long, the Rv0078 binding site is 21 bp long, suggesting Rv0078 binds to DNA differently than TetR.…”

Section: Resultssupporting

confidence: 79%

“…It also remains to be determined what the natural ligand is for Rv0078; while SMARt-420 binds robustly to Rv0078 ( 14 , 15 ), the cytokinin iP did not bind to this TetR-like regulator in our studies. This result may not be surprising when considering SMARt-420 and cytokinins bear no resemblance to each other.…”

Section: Discussionmentioning

confidence: 69%

“…During our ongoing studies, a report was published on the identification of a small molecule of the spiroisoxazoline family, SMARt-420, which strongly induces the expression of the Rv0077c orthologue bcg_0108c in M. bovis bacillus Calmette-Guerin ( 15 ). Using X-ray crystallography and surface plasmon resonance techniques, the authors of this study found SMARt-420 binds to Rv0078 to derepress binding from the Rv0077c promoter ( 14 , 15 ). SMARt-420 was identified in a search for compounds that boost the efficacy of the second-line tuberculosis drug ethionamide (ETH).…”

Section: Resultsmentioning

confidence: 92%

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Cytokinin Signaling in Mycobacterium tuberculosis

Samanovic

Hsu

Jones

et al. 2018

mBio

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It was recently reported that the human-exclusive pathogen Mycobacterium tuberculosis secretes cytokinins, which had only been known as plant hormones. While cytokinins are well-established, adenine-based signaling molecules in plants, they have never been shown to participate in signal transduction in other kingdoms of life. M. tuberculosis is not known to interact with plants. Therefore, we tested the hypothesis that cytokinins trigger transcriptional changes within this bacterial species. Here, we show cytokinins induced the strong expression of the M. tuberculosis gene Rv0077c. We found that Rv0077c expression is repressed by a TetR-like transcriptional repressor, Rv0078. Strikingly, cytokinin-induced expression of Rv0077c resulted in a loss of acid-fast staining of M. tuberculosis. While acid-fast staining is thought to be associated with changes in the bacterial cell envelope and virulence, Rv0077c-induced loss of acid-fastness did not affect antibiotic susceptibility or attenuate bacterial growth in mice, consistent with an unaltered mycolic acid profile of Rv0077c-expressing cells. Collectively, these findings show cytokinins signal transcriptional changes that can affect M. tuberculosis acid-fastness and that cytokinin signaling is no longer limited to the kingdom Plantae.

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Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 92%

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Cytokinin Signaling in Mycobacterium tuberculosis

Samanovic

Hsu

Jones

et al. 2018

mBio

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“…In addition, the overexpression of ethR , a transcriptional regulator that negatively regulates ethA transcription, also increased the ETH‐resistant (Figure 3; Sarin et al, 2021; Tan et al, 2017). Existing studies promote the bactericidal activity of ETH and PTH by inhibiting the function of ethR by developing new drugs, such as Smart‐420 (Blondiaux et al, 2017; Prieri et al, 2018; Wohlkönig et al, 2017).…”

Section: Mechanisms For Drug Resistancementioning

confidence: 99%

Resistance and tolerance of Mycobacterium tuberculosis to antimicrobial agents—How M. tuberculosis can escape antibiotics

Yuan

Duan

2022

WIREs Mechanisms of Disease

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Tuberculosis (TB) poses a serious threat to public health worldwide since it was discovered. Until now, TB has been one of the top 10 causes of death from a single infectious disease globally. The treatment of active TB cases majorly relies on various anti-tuberculosis drugs. However, under the selection pressure by drugs, the continuous evolution of Mycobacterium tuberculosis (Mtb) facilitates the emergence of drug-resistant strains, further resulting in the accumulation of tubercle bacilli with multiple drug resistance, especially deadly multidrug-resistant TB and extensively drug-resistant TB. Researches on the mechanism of drug action and drug resistance of Mtb provide a new scheme for clinical management of TB patients, and prevention of drug resistance. In this review, we summarized the molecular mechanisms of drug resistance of existing anti-TB drugs to better understand the evolution of drug resistance of Mtb, which will provide more effective strategies against drug-resistant TB, and accelerate the achievement of the EndTB Strategy by 2035.

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“…The direct binding of SMARt-420 to EthR 2 was shown by TSA (∆Tm = 1.7°C at 20 µM and 4.0 at 100 µM) and co-crystallization. 75 EthR 2 , like EthR, crystallizes in a homodimeric conformation, with SMARt-420 liganded within the hydrophobic binding domain of each monomer, stabilized by H-bonds with E70 (Figure 9). The dose-dependent inhibition of EthR 2 /DNA interaction was assessed by SPR (IC 50 = 3.3 µM) and a reporter gene assay developed in mammalian cells.…”

Section: Limitations To the Development Of Ethr Inhibitorsmentioning

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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Structural analysis of the interaction between spiroisoxazoline SMARt-420 and the Mycobacterium tuberculosis repressor EthR2

Cited by 10 publications

References 31 publications

Cytokinin Signaling in Mycobacterium tuberculosis

Cytokinin Signaling in Mycobacterium tuberculosis

Resistance and tolerance of Mycobacterium tuberculosis to antimicrobial agents—How M. tuberculosis can escape antibiotics

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

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