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EcoSal Plus

Domain 4:

Synthesis and Processing of Macromolecules

Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules

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  • Authors: Hamed Mosaei1, and Nikolay Zenkin2
  • Editors: Susan T. Lovett3, Deborah Hinton4
    Affiliations: 1: Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK; 2: Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AX, UK; 3: Brandeis University, Waltham, MA; 4: Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MA
  • Received 28 November 2019 Accepted 27 January 2020 Published 27 April 2020
  • Address correspondence to Hamed Mosaei, [email protected]
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  • Abstract:

    RNA polymerases (RNAPs) accomplish the first step of gene expression in all living organisms. However, the sequence divergence between bacterial and human RNAPs makes the bacterial RNAP a promising target for antibiotic development. The most clinically important and extensively studied class of antibiotics known to inhibit bacterial RNAP are the rifamycins. For example, rifamycins are a vital element of the current combination therapy for treatment of tuberculosis. Here, we provide an overview of the history of the discovery of rifamycins, their mechanisms of action, the mechanisms of bacterial resistance against them, and progress in their further development.

  • Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019


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RNA polymerases (RNAPs) accomplish the first step of gene expression in all living organisms. However, the sequence divergence between bacterial and human RNAPs makes the bacterial RNAP a promising target for antibiotic development. The most clinically important and extensively studied class of antibiotics known to inhibit bacterial RNAP are the rifamycins. For example, rifamycins are a vital element of the current combination therapy for treatment of tuberculosis. Here, we provide an overview of the history of the discovery of rifamycins, their mechanisms of action, the mechanisms of bacterial resistance against them, and progress in their further development.

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Image of Figure 1
Figure 1

The ansa chain and naphthalene moiety of molecules are shown in black and blue, respectively.

Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019
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Image of Figure 2
Figure 2

A RIF (with or without groups at C-3/C-4 or KglA) bound at the RIF-binding pocket either sterically blocks progression of the growing RNA chain, resulting in abortive synthesis (left), or inhibits the first phosphodiester bond formation by interfering with initiating NTP or with σ region 3.2 that stabilizes the template DNA.

Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019
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Figure 3

(A) Chemical structures of KglA (in red with C-20 and C-27 side chains highlighted in yellow) and RMP (black). (B) A close-up view of KglA in the RIF-binding pocket of RNAP (PDB: 6CUU). KglA is shown as a stick model (red) with its deoxysugar and succinate groups shown in yellow. RNAP is shown as a transparent surface model (gray), and RNAP β residues, which form the RIF-binding pocket, are shown as stick models. KglA binds to the same residues that RMP binds (cyan) to, with the exception of βF514 (green). KglA makes additional binding with βR143 (blue). (C) A side view of KglA in the RIF-binding pocket shown in panel B (PDB: 1YNN and 6CUU). The RNAP β subunit is shown in cyan. KglA (red and yellow) is overlaid on RMP (gray). Compared with RMP, KglA maintains a larger distance from the RIF-binding pocket (depicted by the two-headed arrow) ( 41 ).

Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019
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Image of Figure 4
Figure 4

The ansa chain and naphthalene moiety of the molecules are shown in black and blue, respectively.

Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019
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Figure 5

(A) Schematic representation of RMP in the stick model (green) bound to residues of RIF-binding pocket (gray stick model; PDBID: 5UAC) ( 48 ). The hydrogen bonds between RMP and residues are shown as dashed lines. Amino acid residues that are mutated in clinical RIF isolates are highlighted in red. The three residues which are most frequently mutated to confer RIF clinical isolates of are marked by an asterisk. (B) The schematic on top represents the primary sequence of the β subunit. The amino acid numbering is depicted. Gray boxes represent the four clusters (RMP resistance-determining regions; RRDRs) where RIF mutations occur. A sequence alignment showing these clusters in , , , , , and is depicted below the schematic bar. Amino acids that are identical to are highlighted in gray. Mutations that confer RIF in are indicated above the sequence.

Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019
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Figure 6

The RNAP core enzyme is illustrated as a transparent surface (α subunits, gray; β subunit, cyan; β′ subunit, bright orange; ω subunit, gray). The active center of RNAP, marked by the presence of catalytic Mg (magenta sphere) is circled. The RMP molecule is depicted as red spheres. Compensatory mutations found on the α, β, and β′ subunits of RNAP are shown as gray, blue, and orange spheres, respectively.

Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019
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Table 1

List of secondary mutations in different RIF bacteria

Citation: Mosaei H, Zenkin N. 2020. Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules, EcoSal Plus 2020; doi:10.1128/ecosalplus.ESP-0017-2019

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