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Guoping Zhao - One of the best experts on this subject based on the ideXlab platform.
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a feedback regulatory model for rifq mediated repression of rifamycin export in amycolatopsis mediterranei
Microbial Cell Factories, 2018Co-Authors: Jingzhi Wang, Guoping Zhao, Jin WangAbstract:Due to the important role of rifamycin in curing tuberculosis infection, the study on rifamycin has never been stopped. Although RifZ, which locates within the rifamycin biosynthetic cluster, has recently been characterized as a pathway-specific regulator for rifamycin biosynthesis, little is known about the regulation of rifamycin export. In this work, we proved that the expression of the rifamycin efflux pump (RifP) was regulated by RifQ, a TetR-family transcriptional regulator. Deletion of rifQ had little impact on bacterial growth, but resulted in improved rifamycin production, which was consistent with the reverse transcription PCR results that RifQ negatively regulated rifP’s transcription. With electrophoretic mobility shift assay and DNase I Footprinting assay, RifQ was found to directly bind to the promoter region of rifP, and a typical inverted repeat was identified within the RifQ-protected sequences. The transcription initiation site of rifP was further characterized and found to be upstream of the RifQ binding sites, well explaining the RifQ-mediated repression of rifP’s transcription in vivo. Moreover, rifamycin B (the end product of rifamycin biosynthesis) remarkably decreased the DNA binding affinity of RifQ, which led to derepression of rifamycin export, reducing the intracellular concentration of rifamycin B as well as its toxicity against the host. Here, we proved that the export of rifamycin B was repressed by RifQ in Amycolatopsis mediterranei, and the RifQ-mediated repression could be specifically relieved by rifamycin B, the end product of rifamycin biosynthesis, based on which a feedback model was proposed for regulation of rifamycin export. With the findings here, one could improve the antibiotic yield by simply inactivating the negative regulator of the antibiotic transporter.
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MOESM8 of A feedback regulatory model for RifQ-mediated repression of rifamycin export in Amycolatopsis mediterranei
2018Co-Authors: Chao Lei, Jingzhi Wang, Guoping Zhao, Yuanyuan Liu, Xinqiang Liu, Jin WangAbstract:Additional file 8: Figure S8. Effect of Rifamycins to the transcription of rifP. Rifamycin SV and rifamycin B were added into the LYZL11 culture medium, respectively, and the rifP transcriptional level was measured at 24Â h after the addition of Rifamycins. DMSO was used as a blank control and rpoB was used as an internal control
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A feedback regulatory model for RifQ-mediated repression of rifamycin export in Amycolatopsis mediterranei
BMC, 2018Co-Authors: Chao Lei, Jingzhi Wang, Guoping Zhao, Yuanyuan Liu, Xinqiang Liu, Jin WangAbstract:Abstract Background Due to the important role of rifamycin in curing tuberculosis infection, the study on rifamycin has never been stopped. Although RifZ, which locates within the rifamycin biosynthetic cluster, has recently been characterized as a pathway-specific regulator for rifamycin biosynthesis, little is known about the regulation of rifamycin export. Results In this work, we proved that the expression of the rifamycin efflux pump (RifP) was regulated by RifQ, a TetR-family transcriptional regulator. Deletion of rifQ had little impact on bacterial growth, but resulted in improved rifamycin production, which was consistent with the reverse transcription PCR results that RifQ negatively regulated rifP’s transcription. With electrophoretic mobility shift assay and DNase I Footprinting assay, RifQ was found to directly bind to the promoter region of rifP, and a typical inverted repeat was identified within the RifQ-protected sequences. The transcription initiation site of rifP was further characterized and found to be upstream of the RifQ binding sites, well explaining the RifQ-mediated repression of rifP’s transcription in vivo. Moreover, rifamycin B (the end product of rifamycin biosynthesis) remarkably decreased the DNA binding affinity of RifQ, which led to derepression of rifamycin export, reducing the intracellular concentration of rifamycin B as well as its toxicity against the host. Conclusions Here, we proved that the export of rifamycin B was repressed by RifQ in Amycolatopsis mediterranei, and the RifQ-mediated repression could be specifically relieved by rifamycin B, the end product of rifamycin biosynthesis, based on which a feedback model was proposed for regulation of rifamycin export. With the findings here, one could improve the antibiotic yield by simply inactivating the negative regulator of the antibiotic transporter
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rifz amed_0655 is a pathway specific regulator for rifamycin biosynthesis in amycolatopsis mediterranei
Applied and Environmental Microbiology, 2017Co-Authors: Chen Li, Zhi Hui Shao, Ying Wang, Guoping Zhao, Jin Wang, Xiaoming DingAbstract:Rifamycin and its derivatives are particularly effective against the pathogenic mycobacteria Mycobacterium tuberculosis and Mycobacterium leprae . Although the biosynthetic pathway of rifamycin has been extensively studied in Amycolatopsis mediterranei , little is known about the regulation in rifamycin biosynthesis. Here, an in vivo transposon system was employed to identify genes involved in the regulation of rifamycin production in A. mediterranei U32. Totally, nine rifamycin-defecient mutants were isolated, among which three mutants had the transposon inserted in AMED_0655 (namely rifZ , encoding a LuxR_family regulator). The rifZ was further knocked out via homologous recombination, and the transcription of genes in the rifamycin biosynthetic gene cluster ( rif cluster) was remarkably reduced in rifZ null mutant. Based on the co-transcription assay results, genes within rif cluster were grouped into ten operons, sharing six promoter regions. With electrophoretic mobility shift assay and DNase I footprinting assay, RifZ was proved to specially bind to all six promoter regions, which was consistent with the fact that RifZ regulated the transcription of whole rif cluster. And the binding consensus sequence was further characterized through alignment using the RifZ-protected DNA sequences. With bioinformatics analysis, another five promoters containing the RifZ box (“CTACC-N8-GGATG”) were identified, among which the binding of RifZ to the promoter regions of both rifK and orf18 ( AMED_0645 ) was further verified. As RifZ directly regulates the transcription of all operons within the rif cluster, we propose that RifZ is a pathway-specific regulator for the rif cluster. Importance To this day, rifamycin and its derivatives are still the first-line anti-tuberculosis drugs. The biosynthesis of rifamycin has been extensively studied and most biosynthetic processes have been characterized. However, little is known about the regulation of the transcription of the rifamycin biosynthetic gene cluster ( rif cluster), and no direct regulator has been characterized before. Through the employment of transposon screening, we here characterized a LuxR-family regulator RifZ as a direct transcriptional activator for rif cluster. As RifZ directly regulates the transcription of all rif genes, it is considered as a pathway-specific regulator for the rif cluster. Therefore, as the first regulator characterized for direct regulation of rif transcription, RifZ may provide a new clue for further engineering of high-yield industrial strains.
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a preliminary study of the mechanism of nitrate stimulated remarkable increase of rifamycin production in amycolatopsis mediterranei u32 by rna seq
Microbial Cell Factories, 2015Co-Authors: Zhi Hui Shao, Jian Xu, Guoping Zhao, Jin WangAbstract:Background Rifamycin is an important antibiotic for the treatment of infectious disease caused by Mycobacteria tuberculosis. It was found that in Amycolatopsis mediterranei U32, an industrial producer for rifamycin SV, supplementation of nitrate into the medium remarkably stimulated the yield of rifamycin SV. However, the molecular mechanism of this nitrate-mediated stimulation remains unknown.
Jin Wang - One of the best experts on this subject based on the ideXlab platform.
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a feedback regulatory model for rifq mediated repression of rifamycin export in amycolatopsis mediterranei
Microbial Cell Factories, 2018Co-Authors: Jingzhi Wang, Guoping Zhao, Jin WangAbstract:Due to the important role of rifamycin in curing tuberculosis infection, the study on rifamycin has never been stopped. Although RifZ, which locates within the rifamycin biosynthetic cluster, has recently been characterized as a pathway-specific regulator for rifamycin biosynthesis, little is known about the regulation of rifamycin export. In this work, we proved that the expression of the rifamycin efflux pump (RifP) was regulated by RifQ, a TetR-family transcriptional regulator. Deletion of rifQ had little impact on bacterial growth, but resulted in improved rifamycin production, which was consistent with the reverse transcription PCR results that RifQ negatively regulated rifP’s transcription. With electrophoretic mobility shift assay and DNase I Footprinting assay, RifQ was found to directly bind to the promoter region of rifP, and a typical inverted repeat was identified within the RifQ-protected sequences. The transcription initiation site of rifP was further characterized and found to be upstream of the RifQ binding sites, well explaining the RifQ-mediated repression of rifP’s transcription in vivo. Moreover, rifamycin B (the end product of rifamycin biosynthesis) remarkably decreased the DNA binding affinity of RifQ, which led to derepression of rifamycin export, reducing the intracellular concentration of rifamycin B as well as its toxicity against the host. Here, we proved that the export of rifamycin B was repressed by RifQ in Amycolatopsis mediterranei, and the RifQ-mediated repression could be specifically relieved by rifamycin B, the end product of rifamycin biosynthesis, based on which a feedback model was proposed for regulation of rifamycin export. With the findings here, one could improve the antibiotic yield by simply inactivating the negative regulator of the antibiotic transporter.
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MOESM8 of A feedback regulatory model for RifQ-mediated repression of rifamycin export in Amycolatopsis mediterranei
2018Co-Authors: Chao Lei, Jingzhi Wang, Guoping Zhao, Yuanyuan Liu, Xinqiang Liu, Jin WangAbstract:Additional file 8: Figure S8. Effect of Rifamycins to the transcription of rifP. Rifamycin SV and rifamycin B were added into the LYZL11 culture medium, respectively, and the rifP transcriptional level was measured at 24Â h after the addition of Rifamycins. DMSO was used as a blank control and rpoB was used as an internal control
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A feedback regulatory model for RifQ-mediated repression of rifamycin export in Amycolatopsis mediterranei
BMC, 2018Co-Authors: Chao Lei, Jingzhi Wang, Guoping Zhao, Yuanyuan Liu, Xinqiang Liu, Jin WangAbstract:Abstract Background Due to the important role of rifamycin in curing tuberculosis infection, the study on rifamycin has never been stopped. Although RifZ, which locates within the rifamycin biosynthetic cluster, has recently been characterized as a pathway-specific regulator for rifamycin biosynthesis, little is known about the regulation of rifamycin export. Results In this work, we proved that the expression of the rifamycin efflux pump (RifP) was regulated by RifQ, a TetR-family transcriptional regulator. Deletion of rifQ had little impact on bacterial growth, but resulted in improved rifamycin production, which was consistent with the reverse transcription PCR results that RifQ negatively regulated rifP’s transcription. With electrophoretic mobility shift assay and DNase I Footprinting assay, RifQ was found to directly bind to the promoter region of rifP, and a typical inverted repeat was identified within the RifQ-protected sequences. The transcription initiation site of rifP was further characterized and found to be upstream of the RifQ binding sites, well explaining the RifQ-mediated repression of rifP’s transcription in vivo. Moreover, rifamycin B (the end product of rifamycin biosynthesis) remarkably decreased the DNA binding affinity of RifQ, which led to derepression of rifamycin export, reducing the intracellular concentration of rifamycin B as well as its toxicity against the host. Conclusions Here, we proved that the export of rifamycin B was repressed by RifQ in Amycolatopsis mediterranei, and the RifQ-mediated repression could be specifically relieved by rifamycin B, the end product of rifamycin biosynthesis, based on which a feedback model was proposed for regulation of rifamycin export. With the findings here, one could improve the antibiotic yield by simply inactivating the negative regulator of the antibiotic transporter
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rifz amed_0655 is a pathway specific regulator for rifamycin biosynthesis in amycolatopsis mediterranei
Applied and Environmental Microbiology, 2017Co-Authors: Chen Li, Zhi Hui Shao, Ying Wang, Guoping Zhao, Jin Wang, Xiaoming DingAbstract:Rifamycin and its derivatives are particularly effective against the pathogenic mycobacteria Mycobacterium tuberculosis and Mycobacterium leprae . Although the biosynthetic pathway of rifamycin has been extensively studied in Amycolatopsis mediterranei , little is known about the regulation in rifamycin biosynthesis. Here, an in vivo transposon system was employed to identify genes involved in the regulation of rifamycin production in A. mediterranei U32. Totally, nine rifamycin-defecient mutants were isolated, among which three mutants had the transposon inserted in AMED_0655 (namely rifZ , encoding a LuxR_family regulator). The rifZ was further knocked out via homologous recombination, and the transcription of genes in the rifamycin biosynthetic gene cluster ( rif cluster) was remarkably reduced in rifZ null mutant. Based on the co-transcription assay results, genes within rif cluster were grouped into ten operons, sharing six promoter regions. With electrophoretic mobility shift assay and DNase I footprinting assay, RifZ was proved to specially bind to all six promoter regions, which was consistent with the fact that RifZ regulated the transcription of whole rif cluster. And the binding consensus sequence was further characterized through alignment using the RifZ-protected DNA sequences. With bioinformatics analysis, another five promoters containing the RifZ box (“CTACC-N8-GGATG”) were identified, among which the binding of RifZ to the promoter regions of both rifK and orf18 ( AMED_0645 ) was further verified. As RifZ directly regulates the transcription of all operons within the rif cluster, we propose that RifZ is a pathway-specific regulator for the rif cluster. Importance To this day, rifamycin and its derivatives are still the first-line anti-tuberculosis drugs. The biosynthesis of rifamycin has been extensively studied and most biosynthetic processes have been characterized. However, little is known about the regulation of the transcription of the rifamycin biosynthetic gene cluster ( rif cluster), and no direct regulator has been characterized before. Through the employment of transposon screening, we here characterized a LuxR-family regulator RifZ as a direct transcriptional activator for rif cluster. As RifZ directly regulates the transcription of all rif genes, it is considered as a pathway-specific regulator for the rif cluster. Therefore, as the first regulator characterized for direct regulation of rif transcription, RifZ may provide a new clue for further engineering of high-yield industrial strains.
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a preliminary study of the mechanism of nitrate stimulated remarkable increase of rifamycin production in amycolatopsis mediterranei u32 by rna seq
Microbial Cell Factories, 2015Co-Authors: Zhi Hui Shao, Jian Xu, Guoping Zhao, Jin WangAbstract:Background Rifamycin is an important antibiotic for the treatment of infectious disease caused by Mycobacteria tuberculosis. It was found that in Amycolatopsis mediterranei U32, an industrial producer for rifamycin SV, supplementation of nitrate into the medium remarkably stimulated the yield of rifamycin SV. However, the molecular mechanism of this nitrate-mediated stimulation remains unknown.
John A Fuerst - One of the best experts on this subject based on the ideXlab platform.
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Discovering the recondite secondary metabolome spectrum of Salinispora species: A study of inter-species diversity. PLoS One 2014, 9, e91488
2016Co-Authors: Utpal Bose, Amitha K Hewavitharana, Nicholas P Shaw, John A Fuerst, A E. Vidgen, Mark P HodsonAbstract:Patterns of inter-species secondary metabolite production by bacteria can provide valuable information relating to species ecology and evolution. The complex nature of this chemical diversity has previously been probed via directed analyses of a small number of compounds, identified through targeted assays rather than more comprehensive biochemical profiling approaches such as metabolomics. Insights into ecological and evolutionary relationships within bacterial genera can be derived through comparative analysis of broader secondary metabolite patterns, and this can also eventually assist biodiscovery search strategies for new natural products. Here, we investigated the species-level chemical diversity of the two marine actinobacterial species Salinispora arenicola and Salinispora pacifica, isolated from sponges distributed across the Great Barrier Reef (GBR), via their secondary metabolite profiles using LC-MS-based metabolomics. The chemical profiles of these two species were obtained by UHPLC-QToF-MS based metabolic profiling. The resultant data were interrogated using multivariate data analysis methods to compare their (bio)chemical profiles. We found a high level of inter-species diversity in strains from these two bacterial species. We also found Rifamycins and saliniketals were produced exclusively by S. arenicola species, as the main secondary metabolites differentiating the two species. Furthermore, the discovery of 57 candidate compounds greatly increases the small number of secondary metabolites previously known to be produced by these species. In addition, we report the production of rifamycin O and W, a key group of ansamycin compounds, in S
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lc ms based metabolomics study of marine bacterial secondary metabolite and antibiotic production in salinispora arenicola
Marine Drugs, 2015Co-Authors: Utpal Bose, Amitha K Hewavitharana, John A Fuerst, Yi Kai Ng, P N Shaw, Mark P HodsonAbstract:An LC-MS-based metabolomics approach was used to characterise the variation in secondary metabolite production due to changes in the salt content of the growth media as well as across different growth periods (incubation times). We used metabolomics as a tool to investigate the production of Rifamycins (antibiotics) and other secondary metabolites in the obligate marine actinobacterial species Salinispora arenicola, isolated from Great Barrier Reef (GBR) sponges, at two defined salt concentrations and over three different incubation periods. The results indicated that a 14 day incubation period is optimal for the maximum production of rifamycin B, whereas rifamycin S and W achieve their maximum concentration at 29 days. A “chemical profile” link between the days of incubation and the salt concentration of the growth medium was shown to exist and reliably represents a critical point for selection of growth medium and harvest time.
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Chromatograms and mass spectra relating to the detection of rifamycin O.
2014Co-Authors: Utpal Bose, Amitha K Hewavitharana, Nicholas P Shaw, John A Fuerst, Miranda E. Vidgen, Mark P HodsonAbstract:(A) LC-QToF-MS Total Ion Chromatogram (TIC) for S. arenicola strain MV0472 and (B) Mass spectrum of peak X and (C) Chromatogram for rifamycin O standard and (D) Mass spectrum of peak X (lower 2 panels). The retention times of X and rifamycin O standard are 24.5 and 24.55 min, respectively. The m/z of molecular ion of X and rifamycin O standards are 752.2985 and 752.2954.
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diversity of mycobacterium species from marine sponges and their sensitivity to antagonism by sponge derived rifamycin synthesizing actinobacterium in the genus salinispora
Fems Microbiology Letters, 2010Co-Authors: Hiroshi Izumi, Marie Gauthier, Amitha K Hewavitharana, Nicholas P Shaw, Bernard M Degnan, John A FuerstAbstract:Eleven isolates of Mycobacterium species as well as an antimycobacterial Salinispora arenicola strain were cultured from the sponge Amphimedon queenslandica. The 16S rRNA, rpoB, and hsp65 genes from these Mycobacterium isolates were sequenced, and phylogenetic analysis of a concatenated alignment showed the formation of a large clade with Mycobacterium poriferae isolated previously from another sponge species. The separation of these Mycobacterium isolates into three species-level groups was evident from sequence similarity and phylogenetic analyses. In addition, an isolate that is phylogenetically related to Mycobacterium tuberculosis was recovered from the sponge Fascaplysinopsis sp. Several different mycobacteria thus appear to co-occur in the same sponge. An actinobacterium closely related to S. arenicola, a known producer of the antimycobacterial Rifamycins, was coisolated from the same A. queenslandica specimen from which mycobacteria had been isolated. This Salinispora isolate was confirmed to synthesize rifamycin and displayed inhibitory effects against representatives from two of three Mycobacterium phylotype groups. Evidence for antagonism of sponge-derived Salinispora against sponge-derived Mycobacterium strains from the same sponge specimen and the production of antimycobacterial antibiotics by this Salinispora strain suggest that the synthesis of such antibiotics may have functions in competition between sponge microbial community members.
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discovery of a new source of rifamycin antibiotics in marine sponge actinobacteria by phylogenetic prediction
Applied and Environmental Microbiology, 2006Co-Authors: Amitha K Hewavitharana, Nicholas P Shaw, John A FuerstAbstract:Phylogenetic analysis of the ketosynthase (KS) gene sequences of marine sponge-derived Salinispora strains of actinobacteria indicated that the polyketide synthase (PKS) gene sequence most closely related to that of Salinispora was the rifamycin B synthase of Amycolatopsis mediterranei. This result was not expected from taxonomic species tree phylogenetics using 16S rRNA sequences. From the PKS sequence data generated from our sponge-derived Salinispora strains, we predicted that such strains might synthesize rifamycin-like compounds. Liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis was applied to one sponge-derived Salinispora strain to test the hypothesis of rifamycin synthesis. The analysis reported here demonstrates that this Salinispora isolate does produce compounds of the rifamycin class, including rifamycin B and rifamycin SV. A rifamycin-specific KS primer set was designed, and that primer set increased the number of rifamycin-positive strains detected by PCR screening relative to the number detectable using a conserved KS-specific set. Thus, the Salinispora group of actinobacteria represents a potential new source of Rifamycins outside the genus Amycolatopsis and the first recorded source of Rifamycins from marine bacteria.
Shashikant Srivastava - One of the best experts on this subject based on the ideXlab platform.
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comparison of Rifamycins for efficacy against mycobacterium avium complex and resistance emergence in the hollow fiber model system
Frontiers in Pharmacology, 2021Co-Authors: Gunavanthi D Boorgula, Laxmi U M R Jakkula, Tawanda Gumbo, Bockgie Jung, Shashikant SrivastavaAbstract:Rifamycins are integral part of the combination regimen for treatment of pulmonary Mycobacterium avium-complex [MAC] infection, but different practitioners prefer different Rifamycins. The objective of the study was to compare microbial kill and resistance emergence of Rifamycins using principles of pharmacokinetics/pharmacodynamics. First, we identified rifamycin MICs in 20 MAC isolates from patients followed by concentration-response studies in test-tubes. Next, we examined efficacy and resistance suppression of three doses of each rifamycin in the hollow fiber system model of pulmonary MAC [HFS-MAC], mimicking human like concentration-time profile of the drugs. HFS-MAC units were repetitively sampled for total and drug-resistant MAC burden and for drug concentration measurements. Inhibitory sigmoid E max model, linear regression, and analysis of variance was used for data analysis. For rifabutin 90% of isolates had MIC ≤ 0.125 mg/L while for both rifampin and rifapentine this was ≤2.0 mg/L. There was no statistically significant difference (p > 0.05) in maximal kill and effective concentration mediating 50% of the bacterial kill among three Rifamycins in the static concentration experiment. In the HFS-MAC, the bactericidal kill (day 0-4) for rifampin was 0.89 (95% Confidence Interval (CI): 0.43-1.35), for rifapentine was 1.05 (95% CI: 0.08-1.23), and for rifabutin was 0.92 (95% CI: 0.61-1.24) log10 CFU/ml, respectively. Rifamycins monotherapy failed after just 4-days of treatment and entire MAC population was drug resistant on day 26 of the study. There was no dose dependent difference in MAC kill or resistance suppression among the three Rifamycins tested in the HFS-MAC. Therefore, replacing one rifamycin, due to emergence of drug-resistance, with other may not be beneficial in clinical setting.
Thomas Dick - One of the best experts on this subject based on the ideXlab platform.
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blocking bacterial naphthohydroquinone oxidation and adp ribosylation improves activity of Rifamycins against mycobacterium abscessus
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Uday S Ganapathy, Tian Lan, Philipp Krastel, Marissa Lindman, Matthew D Zimmerman, Jansy Sarathy, Joanna C Evans, Veronique Dartois, Courtney C Aldrich, Thomas DickAbstract:Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat M. abscessus infections due to poor in vitro activity. While rifabutin, another rifamycin, has better anti-M. abscessus activity, its activity is far from the nanomolar potencies of Rifamycins against M. tuberculosis. Here, we asked i) why is rifabutin more active against M. abscessus than rifampicin, and ii) why is rifabutin's anti-M. abscessus activity poorer than its anti-TB activity. Comparative analysis of naphthoquinone versus naphthohydroquinone-containing Rifamycins suggested that the improved activity of rifabutin over rifampicin is linked to its less readily oxidizable naphthoquinone core. Although rifabutin is resistant to bacterial oxidation, metabolite and genetic analyses showed that this rifamycin is metabolized by the ADP-ribosyltransferase ArrMab like rifampicin, preventing it from achieving the nanomolar activity it displays against M. tuberculosis. Based on the identified dual mechanism of intrinsic rifamycin resistance, we hypothesized that Rifamycins more potent than rifabutin should contain the molecule's naphthoquinone core plus a modification that blocks ADP-ribosylation at its C23. To test these predictions, we performed a blinded screen of a diverse collection of 189 Rifamycins and identified two molecules more potent than rifabutin. As predicted, these compounds contained both a more oxidatively-resistant naphthoquinone core and C25 modifications that blocked ADP-ribosylation. Together, this work revealed dual bacterial metabolism as the mechanism of intrinsic resistance of M. abscessus to Rifamycins and provides proof of concept for the repositioning of Rifamycins for M. abscessus disease by developing derivatives that resist both bacterial oxidation and ADP-ribosylation.
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repositioning Rifamycins for mycobacterium abscessus lung disease
Expert Opinion on Drug Discovery, 2019Co-Authors: Uday S Ganapathy, Veronique Dartois, Thomas DickAbstract:Introduction: The treatment of Mycobacterium abscessus lung disease faces significant challenges due to intrinsic antibiotic resistance. New drugs are needed to cure this incurable disease. The key anti-tubercular rifamycin, rifampicin, suffers from low potency against M. abscessus and is not used clinically. Recently, another member of the rifamycin class, rifabutin, was shown to be active against the opportunistic pathogen. Areas covered: In this review, the authors discuss the Rifamycins as a reemerging drug class for treating M. abscessus infections. The authors focus on the differential potency of rifampicin and rifabutin against M. abscessus in the context of intrinsic antibiotic resistance and bacterial uptake and metabolism. Reports of rifamycin-based drug synergies and rifamycin potentiation by host-directed therapy are evaluated. Expert opinion: While repurposing rifabutin for M. abscessus lung disease may provide some immediate relief, the repositioning (chemical optimization) of Rifamycins offers long-term potential for improving clinical outcomes. Repositioning will require a multifaceted approach involving renewed screening of rifamycin libraries, medicinal chemistry to improve 'bacterial cell pharmacokinetics', better models of bacterial pathophysiology and infection, and harnessing of drug synergies and host-directed therapy towards the development of a better drug regimen.
