Regulation of antibiotic production in Actinobacteria: new perspectives from the post-genomic era.

Heterologous expression of bacterial natural product biosynthetic pathways

Activation of microbial secondary metabolic pathways: Avenues and challenges.

Marine natural products.

The prevalence of multidrug-resistant microbial pathogens due to the continued misuse and overuse of antibiotics in agriculture and medicine is raising the prospect of a return to the preantibiotic days of medicine at the time of diminishing numbers of drug leads. The good news is that an increased understanding of the nature and extent of microbial diversity in natural habitats coupled with the application of new technologies in microbiology and chemistry is opening up new strategies in the search for new specialized products with therapeutic properties. This review explores the premise that harsh environmental conditions in extreme biomes, notably in deserts, permafrost soils and deep-sea sediments select for micro-organisms, especially actinobacteria, cyanobacteria and fungi, with the potential to synthesize new druggable molecules. There is evidence over the past decade that micro-organisms adapted to life in extreme habitats are a rich source of new specialized metabolites. Extreme habitats by their very nature tend to be fragile hence there is a need to conserve those known to be hot-spots of novel gifted micro-organisms needed to drive drug discovery campaigns and innovative biotechnology. This review also provides an overview of microbial-derived molecules and their biological activities focusing on the period from 2010 until 2018, over this time 186 novel structures were isolated from 129 representatives of microbial taxa recovered from extreme habitats.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jam.14386

Extreme environments: microbiology leading to specialized metabolites.

A sulfated glucuronorhamnan from the green seaweed Monostroma nitidum: Characteristics of its structure and antiviral activity.

Actinomycete genome sequencing has disclosed a large number of cryptic secondary metabolite biosynthetic gene clusters. However, their unavailable or limited expression severely hampered the discovery of bioactive compounds. The whiB-like (wbl) regulatory genes play important roles in morphological differentiation as well as secondary metabolism; and hence the wblA
 so
 gene was probed and set as the target to activate cryptic gene clusters in deepsea-derived Streptomyces somaliensis SCSIO ZH66. wblA
 so
 from deepsea-derived S. somaliensis SCSIO ZH66 was inactivated, leading to significant changes of secondary metabolites production in the ΔwblA
 so
 mutant, from which α-pyrone compound violapyrone B (VLP B) was isolated. Subsequently, the VLP biosynthetic gene cluster was identified and characterized, which consists of a type III polyketide synthase (PKS) gene vioA and a regulatory gene vioB; delightedly, inactivation of vioB led to isolation of another four VLPs analogues, among which one was new and two exhibited improved anti-MRSA (methicillin-resistant Staphylococcus aureus, MRSA) activity than VLP B. Moreover, transcriptional analysis revealed that the expression levels of whi genes (whiD, whiG, whiH and whiI) and wbl genes (wblC, wblE, wblH, wblI and wblK) were repressed by different degrees, suggesting an intertwined regulation mechanism of wblA
 so
 in morphological differentiation and secondary metabolism of S. somaliensis SCSIO ZH66. wblA orthologues would be effective targets for activation of cryptic gene clusters in marine-derived Streptomyces strains, notwithstanding the regulation mechanisms might be varied in different strains. Moreover, the availability of the vio gene cluster has enriched the diversity of type III PKSs, providing new opportunities to expand the chemical space of polyketides through biosynthetic engineering.

/pdf/activation-of-a-plasmid-situated-type-iii-pks-gene-cluster-27nbsgtw58.pdf

Activation of a plasmid-situated type III PKS gene cluster by deletion of a wbl gene in deepsea-derived Streptomyces somaliensis SCSIO ZH66

Type III polyketide synthases (PKSs) are simple homodimer ketosynthases that distribute across plants, fungi, and bacteria, catalyzing formation of pyrone- and resorcinol-types aromatic polyketides with various bioactivities. The broad substrate promiscuity displayed by type III PKSs makes them wonderful candidates for expanding chemical diversity of polyketides. Violapyrone B (VLP B, 10), an α-pyrone compound produced by deepsea-derived Streptomyces somaliensis SCSIO ZH66, is encoded by a type III PKS VioA. We overexpressed VioA in three different hosts, including Streptomyces coelicolor M1146, Streptomyces sanyensis FMA as well as the native producer S. somaliensis SCSIO ZH66, leading to accumulation of different violapyrone compounds. Among them, S. coelicolor M1146 served as the host producing the most abundant violapyrones, from which five new (2–4, 7 and 12) and nine known (1, 5, 6, 8–11, 13 and 14) compounds were identified. Anti-influenza A (H1N1) virus activity of these compounds was then evaluated using ribavirin as a positive control (IC50 = 112.9 μM), revealing that compounds 11–14 showed considerable activity with IC50 values of 112.7, 26.9, 106.7 and 28.8 μM, respectively, which are significantly improved as compared to that of VLP B (10) (IC50 > 200 μM). The productions of 10 and 13 were increased by adding P450 inhibitor metyrapone. In addition, site-directed mutagenesis experiment led to demonstration of the residue S242 to be essential for the activity of VioA. Biological background of the expression hosts is an important factor impacting on the encoding products of type III PKSs. By using S. coelicolor M1146 as cell factory, we were able to generate fourteen VLPs compounds. Anti-H1N1 activity assay suggested that the lipophilic nature of the alkyl chains of VLPs plays an important role for the activity, providing valuable guidance for further structural optimization of VLPs.

/pdf/overexpression-of-a-type-iii-pks-gene-affording-novel-2bpf7ig5w3.pdf

Overexpression of a type III PKS gene affording novel violapyrones with enhanced anti-influenza A virus activity.

Antibiotic angucycline derivatives from the deepsea-derived Streptomyces lusitanus.

Sulfonolipids (SoLs) are a unique class of sphingolipids featuring a sulfonate group compared to other sphingolipids. However, the biological functions and biosynthesis of SoLs in human microbiota have been poorly understood. Here, we report the discovery and isolation of SoLs from a human opportunistic pathogen Chryseobacterium gleum DSM16776. We show for the first time the pro-inflammatory activity of SoLs with mice primary macrophages. Furthermore, we used both in vivo heterologous expression and in vitro biochemical reconstitution to characterize two enzymes, cysteate synthase and cysteate fatty acyltransferase, that are specifically involved in the biosynthesis of SoLs rather than other sphingolipids. Based on these two SoL-specific enzymes, our bioinformatics analysis showed a wider distribution of SoL biosynthetic genes in microbes that had not been reported as SoL producers. We selected four of these strains and verified their cysteate synthase and cysteate fatty acyltransferase activities in SoL biosynthesis. Considering this wider distribution of SoL-specific biosynthetic enzymes in the context of SoLs' activity in mediating inflammation, a common and fundamental biological process, it may suggest a more comprehensive function of SoLs at play.

Lukuan Hou

Papers

A sulfated glucuronorhamnan from the green seaweed Monostroma nitidum: Characteristics of its structure and antiviral activity.

Activation of a plasmid-situated type III PKS gene cluster by deletion of a wbl gene in deepsea-derived Streptomyces somaliensis SCSIO ZH66

Overexpression of a type III PKS gene affording novel violapyrones with enhanced anti-influenza A virus activity.

Antibiotic angucycline derivatives from the deepsea-derived Streptomyces lusitanus.

Identification and Biosynthesis of Pro-Inflammatory Sulfonolipids from an Opportunistic Pathogen Chryseobacterium gleum.