A Hybrid NRPS-PKS Gene Cluster Related to the Bleomycin Family of Antitumor Antibiotics in Alteromonas macleodii Strains

Mizuno, Carolina Megumi; Kimes, Nikole E.; López‐Pérez, Mario; Ausó, Eva; Rodrı́guez-Valera, Francisco; Ghai, Rohit

doi:10.1371/journal.pone.0076021

Cited by 30 publications

(27 citation statements)

References 66 publications

(87 reference statements)

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“…2b). As have been previously described, in this flexible region pAMDE1-300 contained a hybrid NRPS-PKS cluster [22] and pGLAAG01 genes involved in metal resistance. However, pASTE61-200 seems that have lost not only most of the gene clusters but also some important tra genes suggesting that this plasmid alone cannot carry out conjugation.…”

Section: Resultsmentioning

confidence: 94%

Networking in microbes: conjugative elements and plasmids in the genus Alteromonas

2017

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BackgroundTo develop evolutionary models for the free living bacterium Alteromonas the genome sequences of isolates of the genus have been extensively analyzed. However, the main genetic exchange drivers in these microbes, conjugative elements (CEs), have not been considered in detail thus far. In this work, CEs have been searched in several complete Alteromonas genomes and their sequence studied to understand their role in the evolution of this genus. Six genomes are reported here for the first time.ResultsWe have found nine different plasmids of sizes ranging from 85 to 600 Kb, most of them were found in a single strain. Networks of gene similarity could be established among six of the plasmids that were also connected with another cluster of plasmids found in Shewanella strains. The cargo genes found in these plasmids included cassettes found before in chromosome flexible genomic islands of Alteromonas strains. We describe also the plasmids pAMCP48-600 and pAMCP49-600, the largest found in Alteromonas thus far (ca. 600 Kb) and containing all the hallmarks to be classified as chromids. We found in them some housekeeping genes and a cluster that code for an exocellular polysaccharide. They could represent the transport vectors for the previously described replacement flexible genomic islands. Integrative and conjugative elements (ICEs) were more common than plasmids and showed similar patterns of variation with cargo genes coding for components of additive flexible genomic islands. A nearly identical ICE was found in A. mediterranea MED64 and Vibrio cholera AHV1003 isolated from a human pathogen, indicating the potential exchange of these genes across phylogenetic distances exceeding the family threshold.ConclusionWe have seen evidence of how CEs can be vectors to transfer gene cassettes acquired in the chromosomal flexible genomic islands, both of the additive and replacement kind. These CEs showed evidence of how genetic material is exchanged among members of the same species but also (albeit less frequently) across genus and family barriers. These gradients of exchange frequency are probably one of the main drivers of species origin and maintenance in prokaryotes and also provide these taxa with large genetic diversity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3461-0) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 94%

Networking in microbes: conjugative elements and plasmids in the genus Alteromonas

2017

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“…The acyltransferase domain of the PKS pathway may have a diverse structure, as reported for Alteromonas macleodii (56), or it could be a trans-acting domain, as reported for X. albilineans and Clostridium spp. (57,58).…”

Section: Discussionmentioning

confidence: 93%

Genomic Insights into the Evolutionary Origin of Xanthomonas axonopodis pv. citri and Its Ecological Relatives

Midha

Patil

2014

Appl Environ Microbiol

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Xanthomonas axonopodis pv. citri (Xac) is the causal agent of citrus bacterial canker (CBC) and is a serious problem worldwide. Like CBC, several important diseases in other fruits, such as mango, pomegranate, and grape, are also caused by Xanthomonas pathovars that display remarkable specificity toward their hosts. While citrus and mango diseases were documented more than 100 years ago, the pomegranate and grape diseases have been known only since the 1950s and 1970s, respectively. Interestingly, diseases caused by all these pathovars were noted first in India. Our genome-based phylogenetic studies suggest that these diverse pathogens belong to a single species and these pathovars may be just a group of rapidly evolving strains. Furthermore, the recently reported pathovars, such as those infecting grape and pomegranate, form independent clonal lineages, while the citrus and mango pathovars that have been known for a long time form one clonal lineage. Such an understanding of their phylogenomic relationship has further allowed us to understand major and unique variations in the lineages that give rise to these pathovars. Whole-genome sequencing studies including ecological relatives from their putative country of origin has allowed us to understand the evolutionary history of Xac and other pathovars that infect fruits.

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“…HAA 01 isolate has both PKS and NRPS genes, thus this isolate may potentially synthesize anticancer compounds from the hybrid NRPS-PKS genes. Some of the bioactive compounds have been reported to be synthesized from such hybrid NRPS-PKS mechanism, including bleomycin (Mizuno et al, 2013), leinamycin (Tang et al, 2006) and curacin A (Chang et al, 2004). Further research is needed to verify the role of these genes in the biosynthesis of anticancer compounds.…”

Section: Discussionmentioning

confidence: 99%

Bioactive Compounds from Sponge Associated Bacteria: Anticancer Activity and NRPS-PKS Gene Expression in Different Carbon Sources

Priyanto

Astuti

Nomura

et al. 2017

American Journal of Biochemistry and Biotechnology

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Sponge associated bacteria with diverse NRPS-PKS genes could be the alternative source of bioactive compounds. This study aimed to analyze the activity as well as the regulatory mechanism regarding the anticancer properties derived from these bacteria against cancer cell lines. Extraction of bacterial metabolites using ethyl acetate solvent resulted yield ranging from 0.003 to 0.016% (w/v). Six extracts of bacterial metabolites showed markedly cytotoxic activity against 8 human hematopoietic cancer cell lines, with IC 50 value 27.24 to 533.73 µg mL −1 in a dose dependent response, as assessed by MTT test. Supporting those results, reduction of cell density, morphological changes including cell shrinkage and formation of the apoptotic body of cancer cells lines, were found. As it might be due to the inhibitory effect of bacterial extract treatment. Apoptosis assay determined by annexin V-FITC apoptosis analysis showed that apoptotic cells were induced by bacterial extract after 6 h of treatment. Thus suggesting that the extract could be one of the external signals that activate the signal transduction pathway of apoptosis, especially in MOLT4 cells, acute lymphoblastic leukemic cell lines. Cell cycle analysis using propidium iodide revealed that the extract HAA 01 caused cell cycle arrest, since most of the MOLT4 cells were accumulated in Sub-G1 phase after 24 h of extract treatment. Interestingly, glycerol, lactose and amylum were the more preferable carbon source to produce anticancer compounds, than glucose. Our study indicates that anticancer activity of HAA 01 (identified as Bacillus subtilis based on API identification) extract is highly correlated with NRPS-PKS gene expression which is likely regulated by the type of carbon source.

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A Hybrid NRPS-PKS Gene Cluster Related to the Bleomycin Family of Antitumor Antibiotics in Alteromonas macleodii Strains

Cited by 30 publications

References 66 publications

Networking in microbes: conjugative elements and plasmids in the genus Alteromonas

Networking in microbes: conjugative elements and plasmids in the genus Alteromonas

Genomic Insights into the Evolutionary Origin of Xanthomonas axonopodis pv. citri and Its Ecological Relatives

Bioactive Compounds from Sponge Associated Bacteria: Anticancer Activity and NRPS-PKS Gene Expression in Different Carbon Sources

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