Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780

Zhao, Xin; Wang, Han; Xue, Zhenglian; Li, Jiansong; Qi, Huan; Zhang, Hui; Zhao, Tian; Wang, Jidong; Xiang, Wensheng

doi:10.1038/s41429-019-0143-6

Cited by 15 publications

(15 citation statements)

References 18 publications

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“…Other examples of structurally related glutarimide‐containing polyketides are cycloheximide that has been used for decades as inhibitor of eukaryotic protein synthesis (Schneider‐Poetsch et al ., 2010; Huang et al ., 2011) and 9‐methylstreptimidone with potential antiviral activity by exerting a protective effect against influenza A2 (H2N2) virus in mice (Saito et al ., 1976). Recently, two new methylstreptimidone analogues have been isolated showing moderate antitumor activity (Zhao et al ., 2019). Apart from antitumor activity against human glioma, streptoglutarimides isolated from a marine actinomycete have also shown antibacterial and antifungal properties (Zhang et al ., 2019).…”

Section: Introductionmentioning

confidence: 99%

Identification of trans‐AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Kačar

Cañedo

Rodríguez

et al. 2021

Environmental Microbiology

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Summary Glutarimide‐containing polyketides are known as potent antitumoral and antimetastatic agents. The associated gene clusters have only been identified in a few Streptomyces producers and Burkholderia gladioli symbiont. The new glutarimide‐family polyketides, denominated sesbanimides D, E and F along with the previously known sesbanimide A and C, were isolated from two marine alphaproteobacteria Stappia indica PHM037 and Labrenzia aggregata PHM038. Structures of the isolated compounds were elucidated based on 1D and 2D homo and heteronuclear NMR analyses and ESI‐MS spectrometry. All compounds exhibited strong antitumor activity in lung, breast and colorectal cancer cell lines. Subsequent whole genome sequencing and genome mining revealed the presence of the trans‐AT PKS gene cluster responsible for the sesbanimide biosynthesis, described as sbn cluster. Strikingly, the modular architecture of downstream mixed type PKS/NRPS, SbnQ, revealed high similarity to PedH in pederin and Lab13 in labrenzin gene clusters, although those clusters are responsible for the production of structurally completely different molecules. The unexpected presence of SbnQ homologues in unrelated polyketide gene clusters across phylogenetically distant bacteria, raises intriguing questions about the evolutionary relationship between glutarimide‐like and pederin‐like pathways, as well as the functionality of their synthetic products.

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Section: Introductionmentioning

confidence: 99%

Identification of trans‐AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Kačar

Cañedo

Rodríguez

et al. 2021

Environmental Microbiology

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“…Other examples of structurally related glutarimide-containing polyketides are cycloheximide that has been used for decades as inhibitor of eukaryotic protein synthesis (9,10) and 9-methylstreptimidone with potential antiviral activity by exerting a protective effect against influenza A2 (H2N2) virus in mice (11). Recently, two new methylstreptimidone analogs have been isolated showing moderate antitumor activity (12). Apart from antitumor activity against human glioma, streptoglutarimides isolated from a marine actinomycete have also shown antibacterial and antifungal properties (13).…”

mentioning

confidence: 99%

“…Known glutarimide polyketides have been isolated from actinomycetes (12)(13)(14)(15)(16) with the exception of recently identified gladiofungin from Burkholderia gladioli (17). Nevertheless, the production of the sesbanimide analogs has been attributed to Gram-negative bacteria, i.e., marine Agrobacterium strains, PH-103 and PH-A034C, isolated from the tunicates Ecteinascidia turbinata collected in Florida and Polycitonidae sp.…”

mentioning

confidence: 99%

Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Kačar

Cañedo

Rodríguez

et al. 2020

Preprint

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Glutaramide-containing polyketides are known as potent antitumoral and antimetastatic agents. However, the associated gene clusters have only been identified and studied in a few Streptomyces producers and sole Burkholderia gladioli symbiont. The new glutaramide-family polyketides, denominated sesbanimides D, E and F along with the previously known sesbanimide A and C, were isolated from two marine alphaproteobacteria Stappia indica PHM037 and Labrenzia aggregata PHM038. Structures of the isolated compounds were elucidated based on 1D and 2D homo and heteronuclear NMR analyses and ESI-MS spectrometry. All compounds exhibited strong antitumor activity in lung, breast and colorectal cancer cell lines. Subsequent whole genome sequencing and genome mining revealed the presence of the trans-AT PKS gene cluster responsible for the sesbanimide biosynthesis, described as sbn cluster, and the sesbanimide modular assembly is proposed. Interestingly, numerous homologous orphan gene clusters were localized in distantly related bacteria and used as comparative genomic assets for a more global characterization of sbn like-clusters. Strikingly, the modular architecture of downstream mixed type PKS/NRPS, SbnQ, revealed high similarity to PedH in pederin and Lab13 in labrenzin gene clusters, although those clusters are responsible for the production of structurally completely different molecules. The unexpected presence of SbnQ homologs in unrelated polyketide gene clusters across phylogenetically distant bacteria, raises intriguing questions about the evolutionary relationship between glutaramide-like and pederin-like pathways, as well as the functionality of their synthetic products.SignificanceGlutaramide-containing polyketides are still a largely understudied group of polyketides, produced mainly by the genera Streptomyces, with a great potential for antitumor drug production. Here, we describe genomes of two cultivable marine bacteria, Stappia indica PHM037 and Labrenzia aggregata PHM038, producers of the cytotoxic glutaramide-family polyketides sesbanimide A and C with chemical elucidation of newly identified analogs D, E and F. Genome mining revealed trans-AT PKS gene cluster responsible for sesbanimide biosynthesis. Although there are numerous homologous gene clusters present in remarkably different bacteria, this is the first time that the biosynthesis product has been reported. The comparative genome analysis reveals stunning, cryptic evolutionary relationship between sesbanimides, glutaramides from Streptomyces spp. and the pederin-family gene clusters.

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“…A recent report by the World Health Organization (WHO) highlights the need to explore novel chemistry from nature amid the increasing problems caused by antimicrobial-resistant (AMR) bacteria [5]. It was previously estimated that there might be billions of microbial species living on earth [6,7] and even from the heavily mined genus of Streptomyces, novel discoveries continue to be made [8][9][10][11][12][13]. Due to the sheer size of microbial and enzymological biodiversity, there exists a vast repertoire of potentially useful compounds remains to be unearthed.…”

Section: Introductionmentioning

confidence: 99%

BiG-SLiCE: A Highly Scalable Tool Maps the Diversity of 1.2 Million Biosynthetic Gene Clusters

Kautsar

Hooft

Ridder

et al. 2020

Preprint

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Genome mining for Biosynthetic Gene Clusters (BGCs) has become an integral part of natural product discovery. The >200,000 microbial genomes now publicly available hold information on abundant novel chemistry. One way to navigate this vast genomic diversity is through comparative analysis of homologous BGCs, which allows identification of cross-species patterns that can be matched to the presence of metabolites or biological activities. However, current tools suffer from a bottleneck caused by the expensive network-based approach used to group these BGCs into Gene Cluster Families (GCFs). Here, we introduce BiG-SLiCE, a tool designed to cluster massive numbers of BGCs. By representing them in Euclidean space, BiG-SLiCE can group BGCs into GCFs in a non-pairwise, near-linear fashion. We used BiG-SLiCE to analyze 1,225,071 BGCs collected from 209,206 publicly available microbial genomes and metagenome-assembled genomes (MAGs) within ten days on a typical 36-cores CPU server. We demonstrate the utility of such analyses by reconstructing a global map of secondary metabolic diversity across taxonomy to identify uncharted biosynthetic potential. BiG-SLiCE also provides a "query mode" that can efficiently place newly sequenced BGCs into previously computed GCFs, plus a powerful output visualization engine that facilitates user-friendly data exploration. BiG-SLiCE opens up new possibilities to accelerate natural product discovery and offers a first step towards constructing a global, searchable interconnected network of BGCs. As more genomes get sequenced from understudied taxa, more information can be mined to highlight their potentially novel chemistry. BiG-SLiCE is available via https://github.com/medema-lab/bigslice.

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Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780

Cited by 15 publications

References 18 publications

Identification of trans‐AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Identification of trans‐AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors

BiG-SLiCE: A Highly Scalable Tool Maps the Diversity of 1.2 Million Biosynthetic Gene Clusters

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