Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules

Mosaei, Hamed; Zenkin, Nikolay

doi:10.1128/ecosalplus.esp-0017-2019

Cited by 24 publications

(18 citation statements)

References 117 publications

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“…A similar mechanism of death can be suggested for rifampin, which also selectively affects the transcription of different genes 116 . It is possible that rifampin, similarly to ribosome-binding antibiotics, reshapes the cellular proteome rather than just blocking global protein synthesis 117 , 118 , but both effects might be synergistic for killing, particularly in species with a low number of rrn operons 3 . Rifamycins do not stimulate the production of hydroxyl radical production, which could contribute to cell death 32 .…”

Section: Specific Antibioticsmentioning

confidence: 99%

Proximate and ultimate causes of the bactericidal action of antibiotics

2020

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During the past 85 years of antibiotic use, we have learned a great deal about how these 'miracle' drugs work. We know the molecular structures and interactions of these drugs and their targets and the effects on the structure, physiology and replication of bacteria. Collectively, we know a great deal about these proximate mechanisms of action for virtually all antibiotics in current use. What we do not know is the ultimate mechanism of action; that is, how these drugs irreversibly terminate the 'individuality' of bacterial cells by removing barriers to the external world (cell envelopes) or by destroying their genetic identity (DNA). Antibiotics have many different 'mechanisms of action' that converge to irreversible lethal effects. In this Perspective, we consider what our knowledge of the proximate mechanisms of action of antibiotics and the pharmacodynamics of their interaction with bacteria tell us about the ultimate mechanisms by which these antibiotics kill bacteria.

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Section: Specific Antibioticsmentioning

confidence: 99%

Proximate and ultimate causes of the bactericidal action of antibiotics

2020

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“…In contrast, ADP-ribosyl-Rif and ADP-ribosyl-KglA were inactive even at high concentrations (100 μM). Because part of the mechanism of inhibition by all rifamycins is the sterical occlusion of the pathway of the nascent RNA ( 13 ), this result suggests that ADP-ribosylation prevents rifamycins binding to RNAP.…”

Section: Resultsmentioning

confidence: 99%

“…Rifamycins inhibit bacterial transcription by targeting the β-subunit of RNAP ( 13 ). One of the findings of this work is that ADP-ribosylation of Rif by Arr proteins completely abolishes its activity against RNAP in vitro .…”

Section: Discussionmentioning

confidence: 99%

Kanglemycin A Can Overcome Rifamycin Resistance Caused by ADP-Ribosylation by Arr Protein

Harbottle

Mosaei

Allenby³

et al. 2021

Antimicrob Agents Chemother

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Rifamycins, such as rifampicin, are potent inhibitors of bacterial RNA polymerases and widely used antibiotics. Usually rifamycin-resistance is associated with mutations in RNAP that preclude rifamycins binding. However, some bacteria have ADP-ribosyl transferases Arr that ADP-ribosylate rifamycin molecules, thus inactivating their antimicrobial activity. Here we directly show that ADP-ribosylation abolishes inhibition of transcription by rifampicin, the most widely used rifamycin antibiotic. We also show that natural rifamycin, Kanglemycin A, which has a unique sugar moiety at the ansa-chain close to the Arr-modification site, does not bind to Arr from M. smegmatis , and thus is not susceptible to inactivation. We, however, found that Kanglemycin A can still be ADP-ribosylated by Arr of an emerging pathogen M. abscessus . Interestingly, the only part of Arr which exhibits no homology between the species is the part that sterically clashes with sugar moiety of Kanglemycin A in M. smegmatis Arr. This suggests that M. abscessus has encountered KglA or rifamycin with similar sugar modification in the course of evolution. The results show that KglA could be effective antimicrobial against some of the Arr encoding bacteria.

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“…Rifabutin is an oral drug that kills mycobacteria by inhibiting the Mtb RNA polymerase [29]. Toxicity was classi ed as low (score 1.5) [30].…”

Section: Selection and Quanti Cation Of Individual Drug Featuresmentioning

confidence: 99%

A machine-learning based model for automated recommendation of individualized treatment of rifampicin-resistant tuberculosis

Verboven

Callens

Black

et al. 2023

Preprint

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Background Rifampicin resistant tuberculosis remains a global health problem with almost half a million new cases annually. In high-income countries patients empirically start a standardized treatment regimen, followed by an individualized regimen guided by drug susceptibility test (DST) results. In most settings, DST information is not available or is limited to isoniazid and fluoroquinolones. Whole genome sequencing could more accurately guide individualized treatment as the full drug resistance profile is obtained with a single test. Whole genome sequencing has not reached its full potential for patient care, in part due to the complexity of translating a resistance profile into the most effective individualized regimen. Methods We developed a treatment recommender clinical decision support system (CDSS) and an accompanying web application for user-friendly recommendation of the optimal individualized treatment regimen to a clinician. Results Following expert stakeholder meetings and literature review, nine drug features and 14 treatment regimen features were identified and quantified. Using machine learning, a model was developed to predict the optimal treatment regimen based on a training set of 3895 treatment regimen-expert feedback pairs. The acceptability of the treatment recommender CDSS was assessed as part of a clinical trial and in a routine care setting. Within the clinical trial setting, all patients received the CDSS recommended treatment. In 8 of 20 cases, the initial recommendation was recomputed because of stock out, clinical contra-indication or toxicity. In routine care setting, physicians rejected the treatment recommendation in 7 out of 15 cases because it deviated from the national TB treatment guidelines. A survey indicated that the treatment recommender CDSS is easy to use and useful in clinical practice but requires digital infrastructure support and training. Conclusions Our findings suggest that global implementation of the novel treatment recommender CDSS holds the potential to improve treatment outcomes of rifampicin resistant tuberculosis.

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Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules

Cited by 24 publications

References 117 publications

Proximate and ultimate causes of the bactericidal action of antibiotics

Proximate and ultimate causes of the bactericidal action of antibiotics

Kanglemycin A Can Overcome Rifamycin Resistance Caused by ADP-Ribosylation by Arr Protein

A machine-learning based model for automated recommendation of individualized treatment of rifampicin-resistant tuberculosis

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