NRPS Substrate Promiscuity Leads to More Potent Antitubercular Sansanmycin Analogues

Xie, Yunying; Cai, Qiang; Ren, Hui; Wang, Lifei; Xu, Hongzhang; Hong, Bin; Wu, Linzhuan; Chen, Ruxian

doi:10.1021/np5001494

Cited by 29 publications

(24 citation statements)

References 20 publications

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“…In the case of different species, as reported in the literature, different substituents could be present in the same class of compounds, leading to different NPs including improvements of their biological activities. 34,35 These results are well explained in Figure 4. The BGCs associated to the Chr1 of B. thailandensis species generally encode information for NRPSs to assembly monomers such as alanine-arginine; cysteinethreonine and ornithine-aspartate-serine; while Chr2 assembles cysteine-cysteine, valine-glycine, and malateaspartate most of the time.…”

supporting

confidence: 63%

“…Different chromosomal levels of similarity could imply directly in monomers flexibility leading to improvements in biosynthetic steps ending in different NPs. 34,35 This could be explained observing different clusters related to the production of thailanstatins. Their different levels of similarity are related to thailanstatins-like compounds with different substituents or side chains.…”

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confidence: 99%

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An Insight Into the Intraspecific Variation of Biosynthetic Gene Clusters Between Strains ofBurkholderia thailandensisspp.

Baldim¹,

Soares²

2016

Journal of the Brazilian Chemical Society

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The present study aimed to investigate the intraspecific variation of biosynthetic gene clusters (BGCs) in different strains of Burkholderia thailandensis in order to guide natural products (NPs) discovery process. Species from the genus Burkholderia are emerging as promising species due to their biosynthetic potential. Through genome-mining strategies, it was able to identify that B. thailandensis strains present major genome variation between chromosomes I and II and the standard. The positioning of BGCs also differs when comparing each chromosome. Classical pathways as well as terpene and bacteriocins were commonly identified to all of them and BGCs related to the production of nonribosomal peptides and polyketides compounds are often noticed. In addition, hybrids BGCs were identified as using large amount of replicon information. Among all species studied, the strain MSMB121 showed greater potential for biosynthesizing novel natural products and after phylogenetic analysis, the likelihood of recognizing sites of novelties was assigned. Keywords: Burkholderia thailandensis, genome-mining, natural products discovery IntroductionSpecies of the genus Burkholderia have emerged as owing promising biosynthetic capability for diverse natural products (NPs). Recently, a remarkable study about the potential of microorganisms in biosynthesizing NPs pointed that proteobacteria species present large number of biosynthetic gene clusters (BGCs).1 This global analysis included species from the genus Pseudomonas spp. and Burkholderia spp. as containing the majority of BGCs counting for proteobacteria representatives. However, the great interest is related to Burkholderia spp., once Pseudomonas spp. are extensively studied. About the likelihood of producing novel NPs, Burkholderia genomes present, statistically, higher percentage of thiotemplate modular systems than those of bacilli, cyanobacteria, myxobacteria and fungi, and is only second to that of actinobacteria.2 These modular systems are related to the production of many classes of pharmaceutical compounds, including polyketide synthase (PKS)-and nonribosomal peptide synthase (NRPS)-related products. 3According to the German Collection of Microorganisms and Cell Cultures (DSMZ) database, the genus Burkholderia comprises more than 90 species. These species inhabit the most diverse types of ecological niches such as soil, water, rhizosphere and plant surface. 4NPs from Burkholderia spp. are structurally and functionally diverse, comprising benzoquinone; lactone; and polyene compounds, lasso peptides, nonribosomal peptides, statins, and polyketides. These compounds present important biological activities. In addition, some of these small molecules from Burkholderia sp. have entered as drug candidates to preclinical evaluation. 5Burkholderia thailandensis (B. thailandensis) E264 presented a high level of similarity to the BGC BTH-II0204-207 from Burkholderia pseudomallei (B. pseudomallei) K96243 related to the production of betulinan/terferol analogues.6 Experiments indicat...

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confidence: 63%

mentioning

confidence: 99%

An Insight Into the Intraspecific Variation of Biosynthetic Gene Clusters Between Strains ofBurkholderia thailandensisspp.

Baldim¹,

Soares²

2016

Journal of the Brazilian Chemical Society

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“…1). To date, several derivatives of uridylpeptide natural products have been generated through engineering of the organisms that produce the natural products or through semi-synthetic approaches and, as such, feature limited structural variation171819202122232425. A number of synthetic studies have also been reported on uridylpeptide natural products and analogues2627282930313233, some of which have been shown to possess antimicrobial activity78.…”

Section: Resultsmentioning

confidence: 99%

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

et al. 2017

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Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

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“…Nevertheless, precursor-directed approaches have also been used to leverage the building bock promiscuity of NRPSs. For example, bicyclic amino acids were fed into the sansamycin Streptomyces producing strain, affording a unique analog with a 8-fold lower MIC against M. tuberculosis [145]. Similarly, pacidamycin biosynthetic machinery was sufficiently promiscuous to generate new derivatives in better yields than the natural pacidamycin simply by feeding tryptophan analogues to the producing strain [46].…”

Section: Promiscuity and Engineering Of Pks/nrps Assembly Linesmentioning

confidence: 99%

Harnessing natural product assembly lines: structure, promiscuity, and engineering

Ladner

Williams

2016

Journal of Industrial Microbiology and Biotechnology

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Many therapeutically relevant natural products are biosynthesized by the action of giant mega-enzyme assembly lines. By leveraging the specificity, promiscuity, and modularity of assembly lines, a variety of strategies have been developed that enable the biosynthesis of modified natural products. This review briefly summarizes recent structural advances related to natural product assembly lines, discusses chemical approaches to probing assembly line structures in the absence of traditional biophysical data, and surveys efforts that harness the inherent or engineered promiscuity of assembly lines for the synthesis of non-natural polyketides and nonribosomal peptide analogues.

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NRPS Substrate Promiscuity Leads to More Potent Antitubercular Sansanmycin Analogues

Cited by 29 publications

References 20 publications

An Insight Into the Intraspecific Variation of Biosynthetic Gene Clusters Between Strains ofBurkholderia thailandensisspp.

An Insight Into the Intraspecific Variation of Biosynthetic Gene Clusters Between Strains ofBurkholderia thailandensisspp.

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Harnessing natural product assembly lines: structure, promiscuity, and engineering

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