SB 205952, a novel semisynthetic monic acid analog with at least two modes of action

Wilson, Jenny; Oliva, B; Cassels, Robert; O’Hanlon, Peter J.; Chopra, Ian

doi:10.1128/aac.39.9.1925

Cited by 17 publications

(18 citation statements)

References 36 publications

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“…One could speculate that the upregulation of genes involved in isoleucine biosynthesis observed in the wild type but not in the rsh syn mutant results in an increased intracellular isoleucine level. Isoleucine can antagonize mupirocin, thereby increasing the MIC of mupirocin in S. aureus (55). Additionally, the rsh syn mutant was not able to survive conditions of amino acid deprivation, indicated by a decrease of CFU.…”

Section: Discussionmentioning

confidence: 99%

Role of the (p)ppGpp Synthase RSH, a RelA/SpoT Homolog, in Stringent Response and Virulence ofStaphylococcus aureus

et al. 2010

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In most bacteria, nutrient limitations provoke the stringent control through the rapid synthesis of the alarmones pppGpp and ppGpp. Little is known about the stringent control in the human pathogen Staphylococcus aureus, partly due to the essentiality of the major (p)ppGpp synthase/hydrolase enzyme RSH (RelA/SpoT homolog). Here, we show that mutants defective only in the synthase domain of RSH (rsh syn ) are not impaired in growth under nutrient-rich conditions. However, these mutants were more sensitive toward mupirocin and were impaired in survival when essential amino acids were depleted from the medium. RSH is the major enzyme responsible for (p)ppGpp synthesis in response to amino acid deprivation (lack of Leu/Val) or mupirocin treatment. Transcriptional analysis showed that the RSH-dependent stringent control in S. aureus is characterized by repression of genes whose products are predicted to be involved in the translation machinery and by upregulation of genes coding for enzymes involved in amino acid metabolism and transport which are controlled by the repressor CodY. Amino acid starvation also provoked stabilization of the RNAs coding for major virulence regulators, such as SaeRS and SarA, independently of RSH. In an animal model, the rsh syn mutant was shown to be less virulent than the wild type. Virulence could be restored by the introduction of a codY mutation into the rsh syn mutant. These results indicate that stringent conditions are present during infection and that RSH-dependent derepression of CodY-regulated genes is essential for virulence in S. aureus.

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Section: Discussionmentioning

confidence: 99%

Role of the (p)ppGpp Synthase RSH, a RelA/SpoT Homolog, in Stringent Response and Virulence ofStaphylococcus aureus

et al. 2010

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“…Although inhibition of RNA synthesis and hence transcription is sufficient to explain why we also observed substantial inhibition of protein synthesis in holomycin-treated cells, an alternative explanation is possible. If holomycin and other pyrrothines inhibit the aminoacylation of one or more tRNA species, then induction of the stringent response would rapidly lead to a shutdown of both RNA and protein synthesis in the cell (1,9,28). Stringency is invoked by an increase in the ratio of uncharged to charged tRNA (1,9,28), which causes a ribosome-bound enzyme, ppGpp synthase I, encoded by relA, to synthesize the regulatory nucleotide ppGpp (guanosine 5Ј, 3Ј-bispyrophosphate).…”

Section: Discussionmentioning

confidence: 99%

“…Stringency is invoked by an increase in the ratio of uncharged to charged tRNA (1,9,28), which causes a ribosome-bound enzyme, ppGpp synthase I, encoded by relA, to synthesize the regulatory nucleotide ppGpp (guanosine 5Ј, 3Ј-bispyrophosphate). Accumulation of this nutritional stress alarmone confers altered promoter specificity on RNA polymerase, resulting not only in suppression of RNA synthesis but also in suppression of the synthesis of proteins and other macromolecules (1,9,28).…”

Section: Discussionmentioning

confidence: 99%

“…Radioactive precursors (1 Ci/ml for 3 H-labeled and 0.1 Ci/ml for 14 C-labeled compounds) were added during the early logarithmic phase and 3 min before the addition of inhibitors at four times their MICs, which were determined by the microdilution method. Incorporation of radioactivity into macromolecules was determined by following previously published procedures from this laboratory (3,4,19,28). For DNA, RNA, and protein synthesis, this involved treatment of cells with trichloroacetic acid (5%, wt/vol) followed by collection of filtrates on glass fiber filters (Whatman GF/C) and quantification of radioactivity by liquid scintillation counting using OptiPhase Safe scintillation fluid (Wallac Ltd.) (3,19,28).…”

Section: Methodsmentioning

confidence: 99%

“…Incorporation of radioactivity into macromolecules was determined by following previously published procedures from this laboratory (3,4,19,28). For DNA, RNA, and protein synthesis, this involved treatment of cells with trichloroacetic acid (5%, wt/vol) followed by collection of filtrates on glass fiber filters (Whatman GF/C) and quantification of radioactivity by liquid scintillation counting using OptiPhase Safe scintillation fluid (Wallac Ltd.) (3,19,28). For determination of lipid synthesis, cells were treated with chloroform and methanol, and radioactivity in the lipid fraction was determined as described previously (4).…”

Section: Methodsmentioning

confidence: 99%

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Antimicrobial Properties and Mode of Action of the Pyrrothine Holomycin

Oliva

O’Neill

Wilson

et al. 2001

Antimicrob Agents Chemother

105

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Holomycin, a member of the pyrrothine class of antibiotics, displayed broad-spectrum antibacterial activity, inhibiting a variety of gram-positive and gram-negative bacteria, with the exception of Enterobacter cloacae, Morganella morganii, and Pseudomonas aeruginosa. The antibiotic lacked activity against the eukaryotic microorganisms Saccharomyces cerevisiae and Candida kefyr. Holomycin exhibited a bacteriostatic response against Escherichia coli that was associated with rapid inhibition of RNA synthesis in whole cells. Inhibition of RNA synthesis could have been a secondary consequence of inhibiting tRNA aminoacylation, thereby inducing the stringent response. However, the levels of inhibition of RNA synthesis by holomycin were similar in a stringent and relaxed pair of E. coli strains that were isogenic except for the deletion of the relA gene. This suggests that inhibition of RNA synthesis by holomycin could reflect direct inhibition of DNA-dependent RNA polymerase. Examination of the effects of holomycin on the kinetics of the appearance of ␤-galactosidase in induced E. coli cells was also consistent with inhibition of RNA polymerase at the level of RNA chain elongation. However, holomycin only weakly inhibited E. coli RNA polymerase in assays using synthetic poly(dA-dT) and plasmid templates. Furthermore, inhibition of RNA polymerase was observed only at holomycin concentrations in excess of those required to inhibit the growth of E. coli. It is possible that holomycin is a prodrug, requiring conversion in the cell to an active species that inhibits RNA polymerase.Thiolutin and holomycin (see Fig. 1) are members of the pyrrothine class of naturally occurring antibiotics that are characterized by the possession of a unique pyrrolinonodithiole nucleus (2). Although these antimicrobial agents were originally discovered more than 40 years ago (6, 13, 23, 26), relatively little is known about their mode of action. Limited studies with thiolutin suggest that the pyrrothines may act as inhibitors of DNA-dependent RNA polymerase. Thus, thiolutin preferentially inhibits RNA synthesis in both Saccharomyces cerevisiae (10) and Escherichia coli (14) and is reported to be a potent inhibitor of partially purified RNA polymerases from S. cerevisiae (10, 25). Furthermore, by monitoring the effects of thiolutin on the induction of ␤-galactosidase in E. coli, Khachatourians and Tipper (14) concluded that the antibiotic interfered with RNA chain elongation rather than with initiation of transcription.However, there are several observations that cast doubt upon the hypothesis that thiolutin, and therefore the pyrrothines as a class, prevents microbial growth by interfering with the elongation of RNA transcripts catalyzed by RNA polymerase. For instance, Sivasubramanian and Jayaraman (24) were unable to reproduce the observations made by Khachatourians and Tipper (14) concerning the effects of thiolutin on ␤-galactosidase induction in E. coli. Thus, these authors (24) concluded that thiolutin inhibits initiation of RNA tran...

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In vitro efficacy of diclofenac against Listeria monocytogenes

Dutta

Mazumdar

Baek

et al. 2008

Eur J Clin Microbiol Infect Dis

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Chemotherapy is often futile in systemic listeriosis, translating to being a peril to public health. There is, thus, an imperative need for novel antilisterial compounds, possibly acting through mechanisms dissimilar to those of existing drugs. The present study describes one such agent-the non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium (Dc). The National Committee for Clinical Laboratory Standards (NCCLS) minimum inhibitory concentration (MIC), mode of action, and two mechanisms of action, i.e., on bacterial DNA and membrane, have been characterized with respect to Dc. The drug showed noteworthy inhibitory action (MIC90 = 50 microg/ml) against Listeria strains, demonstrated cidal (minimum bactericidal concentration [MBC]=100 microg/ml) activity, inhibited listerial DNA synthesis (45.48%; incorporation of [methyl-3H] thymidine), and possessed bacterial membrane-damaging activity (37.33%; BacLight assay). Dc could be used as a lead compound for the synthesis of new, more active agents perhaps devoid of side effects. Further, quantitative structure-activity relationship (QSAR) studies will contribute to a new generation of promising adjuvants to existing antilisterial drugs.

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SB 205952, a novel semisynthetic monic acid analog with at least two modes of action

Cited by 17 publications

References 36 publications

Role of the (p)ppGpp Synthase RSH, a RelA/SpoT Homolog, in Stringent Response and Virulence ofStaphylococcus aureus

Role of the (p)ppGpp Synthase RSH, a RelA/SpoT Homolog, in Stringent Response and Virulence ofStaphylococcus aureus

Antimicrobial Properties and Mode of Action of the Pyrrothine Holomycin

In vitro efficacy of diclofenac against Listeria monocytogenes

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