Benzothiazinones: Prodrugs That Covalently Modify the Decaprenylphosphoryl-β-<scp>d</scp>-ribose 2′-epimerase DprE1 of <i>Mycobacterium tuberculosis</i>

Trefzer, Claudia; Monica, Rengifo-Gonzalez; Hinner, Marlon J.; Schneider, Patricia; Makarov, Vadim; Cole, Stewart T.; Johnsson, Kai

doi:10.1021/ja106357w

Cited by 189 publications

(185 citation statements)

References 16 publications

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“…8,9 The detailed mechanistic and proteomics studies carried out by Makarov and Trefzer et al 6,8,9 have shown that the cysteine at the active site is essential for the anti-TB activity of 1 and 2 and its mutation to any other amino acid resulted in the dramatic loss of activity. Our efforts related to the mechanistic understanding of the reductive activation of 1 suggest that 1 and other related nitroaromatic anti-TB agents may undergo chemical activation of the constituent nitro group to the nitroso intermediate by a cine addition reaction ( Figure 2B).…”

Section: T Uberculosis (Tb) Is a Disease Mainly Caused Bymentioning

confidence: 99%

Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043

Tiwari

Miller

Chiarelli

et al. 2016

ACS Med. Chem. Lett.

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Electron deficient nitroaromatic compounds such as BTZ043 and its closest congener, PBTZ169, and related agents are a promising new class of anti-TB compounds. Herein we report the design and syntheses of 1,3-benzothiazinone azide (BTZ-N 3 ) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N 3 binds in the essentially same pocket as that of BTZ043. Detailed biochemical studies with cell envelope enzyme fractions of Mycobacterium smegmatis combined with our model biochemical reactivity studies with nucleophiles indicated that, in contrast to BTZ043, the azide analogue may have a different mode of activation for anti-TB activity. Subsequent enzymatic studies with recombinant DprE1 from Mtb followed by MIC determination in NTB1 strain of Mtb (harboring Cys387Ser mutation in DprE1 and is BTZ043 resistant) unequivocally indicated that BTZ-N 3 is an effective reversible and noncovalent inhibitor of DprE1.

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Section: T Uberculosis (Tb) Is a Disease Mainly Caused Bymentioning

confidence: 99%

Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043

Tiwari

Miller

Chiarelli

et al. 2016

ACS Med. Chem. Lett.

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“…4 We previously isolated a covalent adduct of DprE1 and BTZ043 from mycobacteria incubated with BTZ043 and proposed a mechanism of action involving reduction of the essential nitro group of BTZ043 to a nitroso group that then reacts with Cys387 of DprE1 to form a stable semimercaptal ( Figure 1A). 7 However, the mechanism of action of BTZs still poses numerous questions, as it is unclear how BTZs are activated and what the basis of the specificity of the proposed nitroso derivative for DprE1 is. Furthermore, it has not been elucidated whether the observed modification of DprE1 indeed affects the activity of DprE1 or functions by inhibiting the activity of DprE2 (or both); neither have the exact roles of DprE1 and DprE2 in the epimerization reaction been validated.…”

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confidence: 99%

Benzothiazinones Are Suicide Inhibitors of Mycobacterial Decaprenylphosphoryl-β-d-ribofuranose 2′-Oxidase DprE1

et al. 2011

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Benzothiazinones (BTZs) are antituberculosis drug candidates with nanomolar bactericidal activity against tubercle bacilli. Here we demonstrate that BTZs are suicide substrates of the FAD-dependent decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase DprE1, an enzyme involved in cell-wall biogenesis. BTZs are reduced by DprE1 to an electrophile, which then reacts in a nearquantitative manner with an active-site cysteine of DprE1, thus providing a rationale for the extraordinary potency of BTZs. Mutant DprE1 enzymes from BTZ-resistant strains reduce BTZs to inert metabolites while avoiding covalent inactivation. Our results explain the basis for drug sensitivity and resistance to an exceptionally potent class of antituberculosis agents.T he increasing number of drug-resistant Mycobacterium tuberculosis strains that fail to respond to first-and secondline drug treatment demands the development of new antituberculosis drugs. 1−3 Benzothiazinones (BTZs) such as BTZ043 ( Figure 1A) are a promising class of new compounds that kill M. tuberculosis in vitro, ex vivo, and in mouse models of tuberculosis. 4 The minimal inhibitory concentration (MIC) of BTZ043 against M. tuberculosis is 1 ng/mL, which is significantly lower than the MICs of all currently used tuberculosis drugs and drug candidates. Decaprenylphosphoryl-β-D-ribofuranose 2′-epimerase was identified as a BTZ target ( Figure 1B). 4 The enzyme is constituted of DprE1 and DprE2 that together catalyze the epimerization of decaprenylphosphoryl-β-D-ribofuranose (DPR) to decaprenylphosphoryl-β-Darabinofuranose (DPA), the arabinosyl donor for the biosynthesis of mycobacterial cell wall arabinan polymers. 4−6 The reaction is believed to proceed via the keto intermediate decaprenylphosphoryl-D-2′-keto-erythro-pentofuranose (DPX) ( Figure 1B). 5 The Cys387Gly and Cys387Ser point mutations in DprE1 result in 250-and 10 000-fold increases in the MIC, respectively. 4 We previously isolated a covalent adduct of DprE1 and BTZ043 from mycobacteria incubated with BTZ043 and proposed a mechanism of action involving reduction of the essential nitro group of BTZ043 to a nitroso group that then reacts with Cys387 of DprE1 to form a stable semimercaptal ( Figure 1A). 7 However, the mechanism of action of BTZs still poses numerous questions, as it is unclear how BTZs are activated and what the basis of the specificity of the proposed nitroso derivative for DprE1 is. Furthermore, it has not been elucidated whether the observed modification of DprE1 indeed affects the activity of DprE1 or functions by inhibiting the activity of DprE2 (or both); neither have the exact roles of DprE1 and DprE2 in the epimerization reaction been validated.A more detailed characterization of the mechanism of action of BTZs requires the availability of pure DprE1 and DprE2. As our previous attempts to purify recombinant DprE1 and DprE2 of M. tuberculosis H37Rv in their active form were unsuccessful,

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“…BTZ043 undergoes nitro-reduction in physiological environment and inhibits DprE1 enzyme covalently through a cysteine residue of the active site. Advantage of this molecule is it doesn't have shown any antagonist action to the other drugs of the anti-TB regimen and as well with some molecules under the trials like, PA-824, SQ109 [43][44][45][46][47][48].…”

Section: New Drugs Approvedmentioning

confidence: 99%

Tuberculosis: Still a Way to go ahead for a Lead- A Review

Bose

Harit

Halder

2017

JAPLR

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Although decades of worship bring a light of new chemical classes and moieties for the treatment of tuberculosis and still running to enlighten more possible ways to withstand and draw a full stop to the condition, the standard reports of tuberculosis enlisting cases are still on the increment side rather to declining state. Since 90s the regimen of anti-TB drugs is well established but now it is under red alters concern as the drugs are resistant to the causative bacilli, M. tuberculosis, endangering mostly the developing countries and disease prone areas of the world. With the motivation of new drug approved for the disease, the moieties in the pipe line for the consideration of being a successful drug, the review also concerns about possible new classes for lead optimization process along with repurposed drugs trial.

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Benzothiazinones: Prodrugs That Covalently Modify the Decaprenylphosphoryl-β-d-ribose 2′-epimerase DprE1 of Mycobacterium tuberculosis

Cited by 189 publications

References 16 publications

Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043

Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043

Benzothiazinones Are Suicide Inhibitors of Mycobacterial Decaprenylphosphoryl-β-d-ribofuranose 2′-Oxidase DprE1

Tuberculosis: Still a Way to go ahead for a Lead- A Review

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