The Biosynthetic Gene Cluster for the β-Lactam Antibiotic Tabtoxin in Pseudomonas syringae

Kinscherf, Thomas G.; Willis, David K.

doi:10.1038/ja.2005.109

Cited by 41 publications

(53 citation statements)

References 20 publications

(19 reference statements)

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“…4a). Notably, unique architectures of bioactive natural products such as medium-sized rings33 ( E , F , I and K ), bridge-head bicyclic structures34 ( J and P ) and β-lactam rings3536 ( G ) were successfully incorporated into the pyrimidine-containing core skeletons. When we overlaid the energy-minimized conformers of each scaffold in 3D space by aligning the pyrimidine substructure, we clearly demonstrated the skeletal diversity and structural complexity of the resulting polyheterocycles (Fig.…”

Section: Resultsmentioning

confidence: 99%

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

et al. 2016

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Diversity-oriented synthesis (DOS) can provide a collection of diverse and complex drug-like small molecules, which is critical in the development of new chemical probes for biological research of undruggable targets. However, the design and synthesis of small-molecule libraries with improved biological relevance as well as maximized molecular diversity represent a key challenge. Herein, we employ functional group-pairing strategy for the DOS of a chemical library containing privileged substructures, pyrimidodiazepine or pyrimidine moieties, as chemical navigators towards unexplored bioactive chemical space. To validate the utility of this DOS library, we identify a new small-molecule inhibitor of leucyl-tRNA synthetase–RagD protein–protein interaction, which regulates the amino acid-dependent activation of mechanistic target of rapamycin complex 1 signalling pathway. This work highlights that privileged substructure-based DOS strategy can be a powerful research tool for the construction of drug-like compounds to address challenging biological targets.

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Section: Resultsmentioning

confidence: 99%

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

et al. 2016

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“…Interestingly, cluster 30 is highly homologous to the gene cluster that controls the biosynthesis of tabtoxin β-lactam in phytopathogenic Pseudomonas syringae (Fig. 2 and Figure S4) 28 . Tabtoxin irreversibly inhibits the enzyme glutamine synthetase causing cells to become intoxicated by high levels of their own unprocessed ammonia causing chlorosis in plants 29 .…”

Section: Resultsmentioning

confidence: 99%

The complete 12 Mb genome and transcriptome of Nonomuraea gerenzanensis with new insights into its duplicated “magic” RNA polymerase

D’Argenio

Petrillo

Pasanisi

et al. 2016

Sci Rep

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In contrast to the widely accepted consensus of the existence of a single RNA polymerase in bacteria, several actinomycetes have been recently shown to possess two forms of RNA polymerases due the to co-existence of two rpoB paralogs in their genome. However, the biological significance of the rpoB duplication is obscure. In this study we have determined the genome sequence of the lipoglycopeptide antibiotic A40926 producer Nonomuraea gerenzanensis ATCC 39727, an actinomycete with a large genome and two rpoB genes, i.e. rpoB(S) (the wild-type gene) and rpoB(R) (the mutant-type gene). We next analyzed the transcriptional and metabolite profiles in the wild-type gene and in two derivative strains over-expressing either rpoB(R) or a mutated form of this gene to explore the physiological role and biotechnological potential of the “mutant-type” RNA polymerase. We show that rpoB(R) controls antibiotic production and a wide range of metabolic adaptive behaviors in response to environmental pH. This may give interesting perspectives also with regard to biotechnological applications.

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“…syringae pv. tabaci by a block of three genes from the tabtoxin-biosynthetic cluster [98,99], one of which (tblR) is deduced to encode an MFS drug transporter. Also present in the cluster is tabP that encodes a hypothetical zinc metalloprotease, perhaps responsible for tabtoxin activation, but there is no candidate b-lactamase gene in the cluster and, curiously, ttr is also absent.…”

Section: Tabtoxinmentioning

confidence: 99%

Avoidance of suicide in antibiotic-producing microbes

Cundliffe

Demain

2010

J Ind Microbiol Biotechnol

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Many microbes synthesize potentially autotoxic antibiotics, mainly as secondary metabolites, against which they need to protect themselves. This is done in various ways, ranging from target-based strategies (i.e. modification of normal drug receptors or de novo synthesis of the latter in drug-resistant form) to the adoption of metabolic shielding and/or efflux strategies that prevent drug-target interactions. These self-defence mechanisms have been studied most intensively in antibiotic-producing prokaryotes, of which the most prolific are the actinomycetes. Only a few documented examples pertain to lower eukaryotes while higher organisms have hardly been addressed in this context. Thus, many plant alkaloids, variously described as herbivore repellents or nitrogen excretion devices, are truly antibiotics-even if toxic to humans. As just one example, bulbs of Narcissus spp. (including the King Alfred daffodil) accumulate narciclasine that binds to the larger subunit of the eukaryotic ribosome and inhibits peptide bond formation. However, ribosomes in the Amaryllidaceae have not been tested for possible resistance to narciclasine and other alkaloids. Clearly, the prevalence of suicide avoidance is likely to extend well beyond the remit of the present article.

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The Biosynthetic Gene Cluster for the β-Lactam Antibiotic Tabtoxin in Pseudomonas syringae

Cited by 41 publications

References 20 publications

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

The complete 12 Mb genome and transcriptome of Nonomuraea gerenzanensis with new insights into its duplicated “magic” RNA polymerase

Avoidance of suicide in antibiotic-producing microbes

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