Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

Wang, Feng; Sambandan, Dhinakaran; Halder, Rajkumar; Wang, Jianbo; Batt, Sarah M.; Weinrick, Brian; Ahmad, Insha; Yang, Pengyu; Zhang, Yong; Kim, John; Hassani, Morad; Huszár, Stanislav; Trefzer, Claudia; Ma, Zhenkun; Kaneko, Takushi; Mdluli, Khisi; Franzblau, Scott G.; Chatterjee, Arnab K.; Johnsson, Kai; Mikušová, Katarı́na; Besra, Gurdyal S.; Fütterer, Klaus; Robbins, Scott H.; Barnes, S. Whitney; Walker, John R.; Jacobs, William R.; Schultz, Peter G.

doi:10.1073/pnas.1309171110

Cited by 204 publications

(228 citation statements)

References 32 publications

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“…M. smegmatis was used to show that lysogenization by bxb1 disrupted a GroEL-1 gene involved in biofilm formation (86). A promising new drug targeting persisters has been identified from screening for compounds inhibiting biofilm formation in M. smegmatis (87). The useful transposon (IS1096) was identified from the genome of mc 2 155 (88) and used to generate valuable auxotrophic mutants of bacillus CalmetteGuérin (89) and the first diverse genetic libraries in M. tuberculosis (90).…”

Section: Discussionmentioning

confidence: 99%

Noncanonical SMC protein in Mycobacterium smegmatis restricts maintenance of Mycobacterium fortuitum plasmids

Panas

Jain

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Research on tuberculosis and leprosy was revolutionized by the development of a plasmid transformation system in the fast-growing surrogate, Mycobacterium smegmatis. This transformation system was made possible by the successful isolation of a M. smegmatis mutant strain mc 2 155, whose efficient plasmid transformation (ept) phenotype supported the replication of Mycobacterium fortuitum pAL5000 plasmids. In this report, we identified the EptC gene, the loss of which confers the ept phenotype. EptC shares significant amino acid sequence homology and domain structure with the MukB protein of Escherichia coli, a structural maintenance of chromosomes (SMC) protein. Surprisingly, M. smegmatis has three paralogs of SMC proteins: EptC and MSMEG_0370 both share homology with Gramnegative bacterial MukB; and MSMEG_2423 shares homology with Gram-positive bacterial SMCs, including the single SMC protein predicted for Mycobacterium tuberculosis and Mycobacterium leprae. Purified EptC was shown to bind ssDNA and stabilize negative supercoils in plasmid DNA. Moreover, an EptC-mCherry fusion protein was constructed and shown to bind to DNA in live mycobacteria, and to prevent segregation of plasmid DNA to daughter cells. To our knowledge, this is the first report of impaired plasmid maintenance caused by a SMC homolog, which has been canonically known to assist the segregation of genetic materials.plasmid segregation | electroporation | DNA topology | partition errors | cell division

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Section: Discussionmentioning

confidence: 99%

Noncanonical SMC protein in Mycobacterium smegmatis restricts maintenance of Mycobacterium fortuitum plasmids

Panas

Jain

Yang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The cross-resistance to the PyrBTZs displayed by the NTB1 strain and the newly generated PyrBTZ01-resistant mutants, due to the Cys387Ser mutation, was unexpected, since Cys387 is required for the binding of covalent nitroaromatic inhibitors, including nitroBTZs, but not noncovalent inhibitors (18). The PyrBTZs with nonsubstituted pyrroles were not expected to form covalent adducts with Cys387.…”

Section: Pyrrole-btz Analogues Are Potent Antimycobacterial Agentsmentioning

confidence: 93%

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

Makarov

Neres

Hartkoorn

et al. 2015

Antimicrob Agents Chemother

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“…Additionally, recent studies identified "non-nitroaromatic" hits that bind to the same pocket as BTZ043 without formation of the covalent semimercaptal adduct. 11 Therefore, synthesis and evaluation of the anti-TB activity of 3 was of interest and is reported herein.…”

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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Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

Cited by 204 publications

References 32 publications

Noncanonical SMC protein in Mycobacterium smegmatis restricts maintenance of Mycobacterium fortuitum plasmids

Noncanonical SMC protein in Mycobacterium smegmatis restricts maintenance of Mycobacterium fortuitum plasmids

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

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

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