Structure-Based Design of Novel Benzoxazinorifamycins with Potent Binding Affinity to Wild-Type and Rifampin-Resistant Mutant <i>Mycobacterium tuberculosis</i> RNA Polymerases

Gill, Sumandeep K.; Xu, Hao; Kirchhoff, Paul D.; Cierpicki, Tomasz; Turbiak, Anjanette J.; Wan, Baojie; Zhang, Nan; Peng, Ke; Franzblau, Scott G.; Garcia, George A.; Showalter, Hollis D.

doi:10.1021/jm201716n

Cited by 23 publications

(36 citation statements)

References 45 publications

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“…Rifalazil also exhibits dramatically reduced Cyp450 induction activity in rat and dog 12 and essentially no hPXR activation in vitro below 100 μM (MIC 90 < 4 nM) 13 .…”

Section: Introductionmentioning

confidence: 98%

“…Since the sequences and antibiotic sensitivities of E. coli and the MTB RNAPs are more similar than those of MTB and Thermus RNAPs 14 , the E. coli RNAP is a better model to study RNAP-antibiotic interactions by X-ray crystallography and for later application of derived information towards TB drug discovery. We have also synthesized a novel subclass of benzoxazinorifamycins (bxRIFs) and established that these analogues generally display superior affinity toward wild-type and Rif R mutants of the MTB RNAP relative to rifalazil 13 . In the present study, we have determined the crystal structures of E. coli RNAP σ 70 holoenzyme complexes with two selected bxRIF derivatives and determined the IC 50 values for those derivatives with the E. coli RNAP to establish a structural basis for further structure-activity relationship studies of bxRIF derivatives against RNAP.…”

Section: Introductionmentioning

confidence: 99%

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X-ray Crystal Structures of the Escherichia coli RNA Polymerase in Complex with Benzoxazinorifamycins

et al. 2013

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Rifampin, a semi-synthetic rifamycin, is the cornerstone of current tuberculosis treatment. Among many semi-synthetic rifamycins, benzoxazinorifamycins have great potential for TB treatment due to their superior affinity for wild-type and rifampin-resistant Mycobacterium tuberculosis RNA polymerases, and their reduced hepatic Cyp450 induction activity. In this study, we have determined the crystal structures of the Escherichia coli RNA polymerase complexes with two benzoxazinorifamycins. The ansa-naphthalene moieties of the benzoxazinorifamycins bind in a deep pocket of the β subunit, blocking the path of the RNA transcript. The C3′-tail of benzoxazinorifamycin fits a cavity between the β subunit and σ factor. We propose that, in addition to blocking RNA exit, the benzoxazinorifamycin C3′-tail changes the σ region3.2 loop position, which influences the template DNA at the active site thereby reducing the efficiency of transcription initiation. This study supports expansion of structure–activity relationships of benzoxazinorifamycins inhibition of RNA polymerase toward uncovering superior analogues with development potential.

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“…Rifalazil also exhibits dramatically reduced Cyp450 induction activity in rat and dog 12 and essentially no hPXR activation in vitro below 100 μM (MIC 90 < 4 nM) 13 .…”

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

X-ray Crystal Structures of the Escherichia coli RNA Polymerase in Complex with Benzoxazinorifamycins

et al. 2013

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“…However, the ease with which resistance to RIF is gained by mutation at multiple sites illustrates that there are significant problems with this site for the development of antimicrobials with long therapeutic lives. While alteration of the RIF binding site does have implications for cell (69,(74)(75)(76). Cocrystal structures showed that the interactions of benzoxazinorifamycins with the RNAP ␤ fork loop II and the 3 loop may occur and may explain the improved biological activity (67,69).…”

Section: Rifamycinsmentioning

confidence: 99%

Bacterial Transcription as a Target for Antibacterial Drug Development

Yang

Lewis

2016

Microbiol Mol Biol Rev

106

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SUMMARYTranscription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design.

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“…However, the development of RZL was suspended as it proved to be toxic in clinical trials [68]. To this end, Showalter et al are conducting an extensive SAR study of benzoxazinorifamycins, RZL derivatives, to identify a compound for further preclinical evaluation [69]. …”

Section: Repurposing: a Shortcut To Success?mentioning

confidence: 99%

The Future for Early-Stage Tuberculosis Drug Discovery

2015

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There is an urgent need for new and better drugs to treat tuberculosis due to lengthy and complex treatment regimens and a rising problem of drug resistance. Drug discovery efforts have increased over the past few years, with a larger focus on modern high-throughput screening technologies. A combination of target-based approaches, with the traditional empirical means of drug identification, has been complemented by the use of target-based phenotypic screens only recently made possibly with newer genetic tools. Using these approaches, a number of promising compound series have been discovered. However, significant problems remain in developing these into drugs. This review highlights recent advances in TB drug discovery, including an overview of screening campaigns, lessons learned and future directions.

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Structure-Based Design of Novel Benzoxazinorifamycins with Potent Binding Affinity to Wild-Type and Rifampin-Resistant Mutant Mycobacterium tuberculosis RNA Polymerases

Cited by 23 publications

References 45 publications

X-ray Crystal Structures of the Escherichia coli RNA Polymerase in Complex with Benzoxazinorifamycins

X-ray Crystal Structures of the Escherichia coli RNA Polymerase in Complex with Benzoxazinorifamycins

Bacterial Transcription as a Target for Antibacterial Drug Development

The Future for Early-Stage Tuberculosis Drug Discovery

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