The Structures of Thiolutin and Aureothricin, Antibiotics Containing a Unique Pyrrolinonodithiole Nucleus

Celmer, Walter D.; Solomons, I. A.

doi:10.1021/ja01615a058

Cited by 103 publications

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“…1a) is a naturally occurring bicyclic dithiole that was first isolated from Streptomyces luteorectiuli based on its antibiotic activities (Celmer and Solomon 1955). Thiolutin inhibits the growth of Saccharomyces cerevisiae and several gram-positive andnegative bacteria (Seneca et al 1952).…”

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Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

Jia

Isenberg

et al. 2010

Cell Stress and Chaperones

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Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

Jia

Isenberg

et al. 2010

Cell Stress and Chaperones

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“…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.…”

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Antimicrobial Properties and Mode of Action of the Pyrrothine Holomycin

Oliva

O’Neill

Wilson

et al. 2001

Antimicrob Agents Chemother

106

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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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“…It has been demonstrated (5) that thiolutin, a sulfur-containing antibiotic produced by Streptomyces luteoreticuli (1), reversibly inhibits growth and ribonucleic acid (RNA) synthesis in Saccharomyces cerevisiae. Minimal inhibitory concentrations also inhibit deoxyribonucleic acid (DNA)-dependent RNA polymerases I, II, and Ill of yeast in vitro (12).…”

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In Vivo Effect of Thiolutin on Cell Growth and Macromolecular Synthesis in Escherichia coli

Khachatourians

Tipper

1974

Antimicrob Agents Chemother

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Thiolutin reversibly inhibits growth and ribonucleic acid synthesis in Saccharomyces cerevisiae . It is now demonstrated that, at 5 μg/ml, thiolutin rapidly inhibits all incorporation of radioactive precursors into ribonucleic acid and protein in Escherichia coli , although the incorporation of deoxythymidine into deoxyribonucleic acid continues for some time. Concentrations of thiolutin of 5 μg/ml and above are bacteriostatic and do not lead to unbalanced growth, so that cell size remains constant. The antibiotic and its inhibitory effects are easily removed by washing, whereupon macromolecular synthesis and cell division resume unimpeded. These data are consistent with reversible inhibition of ribonucleic acid synthesis being the primary mode of action of thiolutin in E. coli , and suggest that thiolutin may be a useful tool for studies where such reversible inhibition is required.

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The Structures of Thiolutin and Aureothricin, Antibiotics Containing a Unique Pyrrolinonodithiole Nucleus

Cited by 103 publications

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Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

Antimicrobial Properties and Mode of Action of the Pyrrothine Holomycin

In Vivo Effect of Thiolutin on Cell Growth and Macromolecular Synthesis in Escherichia coli

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