Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis

Kurabachew, Mekonnen; Lu, Stephen H. J.; Krastel, Philipp; Schmitt, E.; Suresh, B. L.; Goh, Anne; Knox, John E.; Ling, Ngai; Jiricek, Jan; Beer, David; Cynamon, Michael H.; Petersen, Frank; Dartois, Véronique; Keller, Thomas H.; Dick, Thomas; Sambandamurthy, Vasan K.

doi:10.1093/jac/dkn269

Cited by 96 publications

(102 citation statements)

References 20 publications

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“…Drug Susceptibility Testing-Bacterial drug susceptibility was determined in 7H9 medium as described previously (12). Briefly, compounds dissolved in 90% DMSO were 2-fold serialdiluted in duplicates and spotted in 96-well clear plates, resulting in 10 -12 dilutions of each compound.…”

Section: Methodsmentioning

confidence: 99%

para-Aminosalicylic Acid Is a Prodrug Targeting Dihydrofolate Reductase in Mycobacterium tuberculosis

Zheng

Rubín

Bifani

et al. 2013

Journal of Biological Chemistry

171

115

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Background: PAS is an antimycobacterial whose mechanism(s) of action remains elusive. Results: PAS is incorporated into the folate pathway by DHPS-DHFS, generating an anti-metabolite. DHFS and RibD are associated with PAS resistance. Conclusion: Hydroxyl dihydrofolate inhibits DHFR. folC and ribD are drug target genes for identification of clinical PAS resistance. Significance: Metabolite analog incorporation into essential biosynthetic pathways is promising for developing antibacterials.

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Section: Methodsmentioning

confidence: 99%

para-Aminosalicylic Acid Is a Prodrug Targeting Dihydrofolate Reductase in Mycobacterium tuberculosis

Zheng

Rubín

Bifani

et al. 2013

Journal of Biological Chemistry

171

115

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“…ORG 1620 with increased fidaxomicin MIC (1 mg l 21 ) was generated through a single-step exposure of ATCC 9689 to a high concentration of fidaxomicin and had a single mutation in the rpoB region of the RNA polymerase (Gln 1074 ALys). The latter amino acid mutation has been identified at homologous positions in other species with a low susceptibility to lipiarmycin, a related macrocyclic compound (Kurabachew et al, 2008;Mekler et al, 2004). Despite a several-fold higher MIC compared with the parental strains, both strains with mutations in the RNA polymerase were rapidly killed by fidaxomicin at 46 MIC concentrations, indicating that mutants that may arise during fidaxomicin therapy will probably be eliminated by the high levels of drug achieved in the gut.…”

Section: Killing Kineticsmentioning

confidence: 99%

Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile

Babakhani

Gomez

Robert

et al. 2011

Journal of Medical Microbiology

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The kinetics of bacterial killing for fidaxomicin and its major metabolite, OP-1118, were investigated against Clostridium difficile strains, including two clinical strains belonging to the restriction endonuclease analysis group BI (ORG 1687 and 1698), the ATCC 43255 strain and two laboratory-derived mutant strains with decreased susceptibility to fidaxomicin (ORG 919 and 1620). Both fidaxomicin and OP-1118 demonstrated time-dependent killing of C. difficile strains. Fidaxomicin (at 4¾ MIC) reduced bacterial counts of the ATCC 43255 strain, clinical strain ORG 1687 and the two laboratory-generated mutant strains by ¢3 logs within 48 h of exposure. The other BI strain, ORG 1698, was tested at 2¾ MIC fidaxomicin with bacterial counts decreasing 1 log in 48 h. Exposure to OP-1118 (at 4¾ MIC) also resulted in a ¢3 log drop in c.f.u. counts for the ATCC 43255 strain, the clinical BI strain ORG 1687 and the mutant strain ORG 919. Higher concentrations of OP-1118 (32¾ MIC) were required for a 3 log reduction in c.f.u. counts for the other BI strain, ORG 1698. In summary, the results indicate that both fidaxomicin and its major metabolite, OP-1118, are bactericidal against C. difficile strains, including the hypervirulent restriction endonuclease analysis group BI strains, at concentrations that are many fold below the detected faecal concentrations of these compounds after oral administration of fidaxomicin.

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“…Lipiarmycin A3 and related macrocyclic polyketides purified from a Catellatospora strain of the actinomycetes group exhibited excellent inhibitory activity against multidrug-resistant strains of MTB with MIC values below 0.1 µg/ml. Sequence analysis of the rpoB and rpoC genes from spontaneous lipiarmycinresistant mutants of MTB revealed that missense mutations in these genes caused resistance to lipiarmycin [31]. Although both lipiarmycin and rifampicin are known to inhibit the bacterial RNA polymerase, the sites of mutation in the rpoB gene were found to be different in MTB strains resistant to these inhibitors.…”

Section: Antibioticsmentioning

confidence: 99%

Natural products as probes in pharmaceutical research

Schmitt

Hoepfner

Krastel

2016

Journal of Industrial Microbiology and Biotechnology

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From the start of the pharmaceutical research natural products played a key role in drug discovery and development. Over time many discoveries of fundamental new biology were triggered by the unique biological activity of natural products. Unprecedented chemical structures, novel chemotypes, often pave the way to investigate new biology and to explore new pathways and targets. This review summarizes the recent results in the area with a focus on research done in the laboratories of Novartis Institutes for BioMedical Research. We aim to put the technological advances in target identification techniques in the context to the current revival of phenotypic screening and the increasingly complex biological questions related to drug discovery.

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Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis

Cited by 96 publications

References 20 publications

para-Aminosalicylic Acid Is a Prodrug Targeting Dihydrofolate Reductase in Mycobacterium tuberculosis

para-Aminosalicylic Acid Is a Prodrug Targeting Dihydrofolate Reductase in Mycobacterium tuberculosis

Killing kinetics of fidaxomicin and its major metabolite, OP-1118, against Clostridium difficile

Natural products as probes in pharmaceutical research

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