Resistance of Escherichia coli to rifampicin and sorangicin A - a comparison.

Römmele, Günter; Wirz, Gabriela; Solf, Renate; Vosbeck, K; Gruner, J.; Wehrli, W.

doi:10.7164/antibiotics.43.88

Cited by 20 publications

(18 citation statements)

References 9 publications

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“…In view of their structural novelty these agents might therefore be expected to retain activity against rifampin-resistant isolates. However, there have been reports of cross-resistance between some of the older compounds described here and rifampin (13,24). We examined this in more detail by establishing whether the nonrifamycin-type RNA polymerase inhibitors were active against genetically defined rifampicin-resistant (rpoB) mutants of S. aureus.…”

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confidence: 99%

“…Therefore, before considering whether other RNA polymerase inhibitors might be developed, it is important to establish whether resistance to rifamycins, such as rifampin, also confers cross-resistance to the other agents. Some attempts to address this issue have been made (9,12,13,15,24). However, the data are incomplete and the genetic basis of resistance to rifamycins in those strains used for cross-screening has rarely been determined.…”

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confidence: 99%

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RNA Polymerase Inhibitors with Activity against Rifampin-Resistant Mutants of Staphylococcus aureus

O’Neill¹,

Oliva

Storey³

et al. 2000

Antimicrob Agents Chemother

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A collection of rifampin-resistant mutants of Staphylococcus aureus with characterized RNA polymerase ␤-subunit (rpoB) gene mutations was cross-screened against a number of other RNA polymerase inhibitors to correlate susceptibility with specific rpoB genotypes. The rpoB mutants were cross-resistant to streptolydigin and sorangicin A. In contrast, thiolutin, holomycin, corallopyronin A, and ripostatin A retained activity against the rpoB mutants. The second group of inhibitors may be of interest as drug development candidates.Bacterial DNA-dependent RNA polymerase is an attractive drug target because RNA chain elongation is essential for bacterial growth (6, 16). Among those antibiotics discovered in the last 50 years, there are several known, or suspected, inhibitors of bacterial DNA-dependent RNA polymerase that have not been developed and could be candidates for new drugs. These agents include thiolutin (18), holomycin (B. Oliva, A. O'Neill, J. M. Wilson, P. J. O'Hanlon and I. Chopra, submitted for publication), streptolydigin (6, 16), the ripostatins, corallopyronins and sorangicins (10-12, 23) (Fig. 1). However, bacterial resistance has already developed to the rifamycins, the only class of RNA polymerase inhibitor that is in use clinically (21). Therefore, before considering whether other RNA polymerase inhibitors might be developed, it is important to establish whether resistance to rifamycins, such as rifampin, also confers cross-resistance to the other agents. Some attempts to address this issue have been made (9,12,13,15,24). However, the data are incomplete and the genetic basis of resistance to rifamycins in those strains used for cross-screening has rarely been determined. Furthermore, some data are contradictory; e.g., cross-resistance between rifampin and streptolydigin has been observed by some authors (13) but not by others (9,15).To assist the evaluation of these older agents we crossscreened them against a collection of rifampin-resistant mutants of Staphylococcus aureus, generated in an isogenic background, with defined RNA polymerase ␤-subunit (rpoB) gene mutations. These S. aureus strains, which provide a model for rpoB mutations occurring in naturally occurring isolates of staphylococci and other organisms (1,7,8,15,22,28,29), have allowed us to correlate susceptibility with specific rpoB genotypes.The antibiotics used here were either purchased from Sigma (rifampin and streptolydigin) or were gifts from H. Reichenbach, Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany (corallopyronin A, ripostatin A, and sorangicin A); P. O'Hanlon, SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom (holomycin and thiolutin); and Pharmacia & Upjohn (rifabutin). Spontaneous rifampin-resistant mutants of S. aureus 8325-4 (20) were isolated by plating approximately 10 8 CFU onto Iso-Sensitest agar (Oxoid, Basingstoke, United Kingdom) containing 0.032 g of rifampin/ml (four times the MIC). A number of rifampin-resistant mutants were picked at random, and their MICs of rifampin were d...

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confidence: 99%

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confidence: 99%

RNA Polymerase Inhibitors with Activity against Rifampin-Resistant Mutants of Staphylococcus aureus

O’Neill¹,

Oliva

Storey³

et al. 2000

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…It has also been observed that some rifampin-resistant mutations can confer sorangicin resistance, suggesting largely overlapping binding sites for these two drugs (31,127,145). However, the structures of these drugs are different and observation that some rifampin-resistant mutants are sorangicin sensitive, while most sorangicin-resistant mutations confer rifampin resistance, suggests that subtle differences exist with regard to their modes of action (145).…”

Section: Drug-resistant Rnap Mutantsmentioning

confidence: 99%

Structural Perspective on Mutations Affecting the Function of Multisubunit RNA Polymerases

Trinh

Langelier

Archambault

et al. 2006

Microbiol Mol Biol Rev

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SUMMARY High-resolution crystallographic structures of multisubunit RNA polymerases (RNAPs) have increased our understanding of transcriptional mechanisms. Based on a thorough review of the literature, we have compiled the mutations affecting the function of multisubunit RNA polymerases, many of which having been generated and studied prior to the publication of the first high-resolution structure, and highlighted the positions of the altered amino acids in the structures of both the prokaryotic and eukaryotic enzymes. The observations support many previous hypotheses on the transcriptional process, including the implication of the bridge helix and the trigger loop in the processivity of RNAP, the importance of contacts between the RNAP jaw-lobe module and the downstream DNA in the establishment of a transcription bubble and selection of the transcription start site, the destabilizing effects of ppGpp on the open promoter complex, and the link between RNAP processivity and termination. This study also revealed novel, remarkable features of the RNA polymerase catalytic mechanisms that will require additional investigation, including the putative roles of fork loop 2 in the establishment of a transcription bubble, the trigger loop in start site selection, and the uncharacterized funnel domain in RNAP processivity.

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“…2), suggesting that the former might be able to adapt better than RIF to conformational change and mutations in RNAP (80). Studies on RIF and sorangicin against resistant mutant M. tuberculosis strains revealed that a narrower range of mutant strains were resistant to sorangicin than to RIF and proved that RIF was more sensitive to the change of shape of the binding pocket due to its rigid structure, while sorangicin displayed more conformational flexibility, as demonstrated by molecular dynamics simulations (80,82).…”

Section: Sorangicinmentioning

confidence: 99%

Bacterial Transcription as a Target for Antibacterial Drug Development

Yang

Lewis

2016

Microbiol Mol Biol Rev

113

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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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Resistance of Escherichia coli to rifampicin and sorangicin A - a comparison.

Cited by 20 publications

References 9 publications

RNA Polymerase Inhibitors with Activity against Rifampin-Resistant Mutants of Staphylococcus aureus

RNA Polymerase Inhibitors with Activity against Rifampin-Resistant Mutants of Staphylococcus aureus

Structural Perspective on Mutations Affecting the Function of Multisubunit RNA Polymerases

Bacterial Transcription as a Target for Antibacterial Drug Development

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