Despite the importance of microbial natural products for human health, only a few bacterial genera have been mined for the new natural products needed to overcome the urgent threat of antibiotic ...resistance. This is surprising, given that genome sequencing projects have revealed that the capability to produce natural products is not a rare feature among bacteria. Even the bacteria occurring in the human microbiome produce potent antibiotics, and thus potentially are an untapped resource for novel compounds, potentially with new activities. This review highlights examples of bacteria that should be considered new sources of natural products, including anaerobes, pathogens, and symbionts of humans, insects, and nematodes. Exploitation of these producer strains, combined with advances in modern natural product research methodology, has the potential to open the way for a new golden age of microbial therapeutics.
Insects are not only the most diverse group of animals on our planet, but also a huge reservoir for unusual microorganism which are a rich source of pharmaceutically interesting natural products. ...This review focuses on recent advances in the understanding of secondary metabolism of
Bacillus thuringiensis,
Pseudomonas entomophila, and
Xenorhabdus and
Photorhabdus bacteria all of which are entomopathogenic. Genome-sequencing projects revealed the capacity of these bacteria to produce several different secondary metabolites including peptides, polyketides, and hybrids of both. This richness for interesting compounds is reflected by an increasing number of compounds that have been identified from these bacteria as discussed in this review.
Parasitic nematodes infect different species of animals and plants. Root-knot nematodes are members of the genus Meloidogyne, which is distributed worldwide and parasitizes numerous plants, including ...vegetables, fruits, and crops. To reduce the global burden of nematode infections, only a few chemical therapeutic classes are currently available. The majority of nematicides are prohibited due to their harmful effects on the environment and public health. This study was intended to identify new nematicidal natural products (NPs) from the bacterial genus Xenorhabdus, which exists in symbiosis with Steinernema nematodes. Cell-free culture supernatants of Xenorhabdus bacteria were used for nematicidal bioassay, and high mortality rates for Caenorhabditis elegans and Meloidogyne javanica were observed. Promoter exchange mutants of biosynthetic gene clusters encoding nonribosomal peptide synthetases (NRPS) or NRPS-polyketide synthase hybrids in Xenorhabdus bacteria carrying additionally a hfq deletion produce a single NP class, which have been tested for their bioactivity. Among the NPs tested, fabclavines, rhabdopeptides, and xenocoumacins were highly toxic to nematodes and resulted in mortalities of 95.3, 74.6, and 72.6% to C. elegans and 82.0, 90.0, and 85.3% to M. javanica, respectively. The findings of such nematicidal NPs can provide templates for uncovering effective and environmentally safe alternatives to commercially available nematicides.
Dialkylresorcinols as bacterial signaling molecules Brameyer, Sophie; Kresovic, Darko; Bode, Helge B. ...
Proceedings of the National Academy of Sciences - PNAS,
01/2015, Letnik:
112, Številka:
2
Journal Article
Recenzirano
Odprti dostop
It is well recognized that bacteria communicate via small diffusible molecules, a process termed quorum sensing. The best understood quorum sensing systems are those that use acylated homoserine ...lactones (AHLs) for communication. The prototype of those systems consists of a LuxI-like AHL synthase and a cognate LuxR receptor that detects the signal. However, many proteobacteria possess LuxR receptors, yet lack any LuxI-type synthase, and thus these receptors are referred to as LuxR orphans or solos. In addition to the well-known AHLs, little is known about the signaling molecules that are sensed by LuxR solos. Here, we describe a novel cell–cell communication system in the insect and human pathogen Photorhabdus asymbiotica . We identified the LuxR homolog PauR to sense dialkylresorcinols (DARs) and cyclohexanediones (CHDs) instead of AHLs as signals. The DarABC synthesis pathway produces the molecules, and the entire system emerged as important for virulence. Moreover, we have analyzed more than 90 different Photorhabdus strains by HPLC/MS and showed that these DARs and CHDs are specific to the human pathogen P. asymbiotica . On the basis of genomic evidence, 116 other bacterial species are putative DAR producers, among them many human pathogens. Therefore, we discuss the possibility of DARs as novel and widespread bacterial signaling molecules and show that bacterial cell–cell communication goes far beyond AHL signaling in nature.
Significance Bacteria can communicate with each other by small diffusible molecules, a process termed quorum sensing. Many bacteria use acylated homoserine lactones (AHLs) as signals, which are sensed by so-called LuxR-type receptors. With the photopyrones from the insect pathogenic bacterium Photorhabdus luminescens , we recently identified the first quorum sensing molecules different from AHLs that are sensed by a LuxR-type receptor. Here we describe the second novel quorum sensing molecule sensed by a LuxR-type receptor of Photorhabdus species, PauR of the human pathogen Photorhabdus asymbiotica . We demonstrate that P. asymbiotica communicates via dialkylresorcinols (DARs) and cyclohexanediones (CHDs). As the synthesis pathway is widespread, and often present in human pathogens, we discuss DARs and CHDs as novel and widespread signaling molecules.
The interaction in multisubunit non‐ribosomal peptide synthetases (NRPSs) is mediated by docking domains that ensure the correct subunit‐to‐subunit interaction. We introduced natural docking domains ...into the three‐module xefoampeptide synthetase (XfpS) to create two to three artificial NRPS XfpS subunits. The enzymatic performance of the split biosynthesis was measured by absolute quantification of the products by HPLC‐ESI‐MS. The connecting role of the docking domains was probed by deleting integral parts of them. The peptide production data was compared to soluble protein amounts of the NRPS using SDS‐PAGE. Reduced peptide synthesis was not a result of reduced soluble NRPS concentration but a consequence of the deletion of vital docking domain parts. Splitting the xefoampeptide biosynthesis polypeptide by introducing docking domains was feasible and resulted in higher amounts of product in one of the two tested split‐module cases compared to the full‐length wild‐type enzyme.
A breed apart: The non‐ribosomal peptide synthetase (NRPS) XfpS, which produces the peptides xefoampeptides A and B, can be artificially split without loss of biosynthetic activity by introducing docking domains into XfpS. In fact, in this case, the production of both peptides from the split system increased compared to product levels from the full‐length XfpS. Splitting XfpS into three subunits also led to a functional NRPS system.
Covering: up to November 2017 Organismic interaction is one of the fundamental principles for survival in any ecosystem. Today, numerous examples show the interaction between microorganisms like ...bacteria and higher eukaryotes that can be anything between mutualistic to parasitic/pathogenic symbioses. There is also increasing evidence that microorganisms are used by higher eukaryotes not only for the supply of essential factors like vitamins but also as biological weapons to protect themselves or to kill other organisms. Excellent examples for such systems are entomopathogenic nematodes of the genera Heterorhabditis and Steinernema that live in mutualistic symbiosis with bacteria of the genera Photorhabdus and Xenorhabdus, respectively. Although these systems have been used successfully in organic farming on an industrial scale, it was only shown during the last 15 years that several different natural products (NPs) produced by the bacteria play key roles in the complex life cycle of the bacterial symbionts, the nematode host and the insect prey that is killed by and provides nutrients for the nematode-bacteria pair. Since the bacteria can switch from mutualistic to pathogenic lifestyle, interacting with two different types of higher eukaryotes, and since the full system with all players can be established in the lab, they are promising model systems to elucidate the natural function of microbial NPs. This review summarizes the current knowledge as well as open questions for NPs from Photorhabdus and Xenorhabdus and tries to assign their roles in the tritrophic relationship.
The production of natural product compound libraries has been observed in nature for different organisms such as bacteria, fungi and plants; however, little is known about the mechanisms generating ...such chemically diverse libraries. Here we report mechanisms leading to the biosynthesis of the chemically diverse rhabdopeptide/xenortide peptides (RXPs). They are exclusively present in entomopathogenic bacteria of the genera Photorhabdus and Xenorhabdus that live in symbiosis with nematodes delivering them to insect prey, which is killed and utilized for nutrition by both nematodes and bacteria. Chemical diversity of the biologically active RXPs results from a combination of iterative and flexible use of monomodular nonribosomal peptide synthetases including substrate promiscuity, enzyme cross-talk and enzyme stoichiometry as shown by in vivo and in vitro experiments. Together, this highlights several of nature's methods for diversification, or evolution, of natural products and sheds light on the biosynthesis of the bioactive RXPs.
In recent years, research in the field of Microbial Ecology has revealed the tremendous diversity and complexity of microbial communities across different ecosystems. Microbes play a major role in ...ecosystem functioning and contribute to the health and fitness of higher organisms. Scientists are now facing many technological and methodological challenges in analyzing these complex natural microbial communities. The advances in analytical and omics techniques have shown that microbial communities are largely shaped by chemical interaction networks mediated by specialized (water-soluble and volatile) metabolites. However, studies concerning microbial chemical interactions need to consider biotic and abiotic factors on multidimensional levels, which require the development of new tools and approaches mimicking natural microbial habitats. In this review, we describe environmental factors affecting the production and transport of specialized metabolites. We evaluate their ecological functions and discuss approaches to address future challenges in microbial chemical ecology (MCE). We aim to emphasize that future developments in the field of MCE will need to include holistic studies involving organisms at all levels and to consider mechanisms underlying the interactions between viruses, micro-, and macro-organisms in their natural environments.
The pyrrolobenzodiazepine tilivalline (1) was originally identified in the human gut pathobiont Klebsiella oxytoca, the causative agent of antibiotic-associated hemorrhagic colitis. Here we show the ...identification of tilivalline and analogs thereof in the entomopathogenic bacterium Xenorhabdus eapokensis as well as the identification of its biosynthesis gene cluster encoding a bimodular non-ribosomal peptide synthetase. Heterologous expression of both genes in E. coli resulted in the production of 1 and from mutasynthesis and precursor directed biosynthesis 11 new tilivalline analogs were identified in X. eapokensis. These results allowed the prediction of the tilivalline biosynthesis being similar to that in K. oxytoca.
Gut reaction: There is increasing evidence that the impact on human health and disease of the microbes living in and on us has been underestimated. Several of the small molecules produced by “our” ...bacteria are structurally highly complex and show unusual biosynthetic pathways or modes of action, as highlighted by the race to elucidate the structure and biosynthesis of colibactin, a genotoxic compound produced by human gut bacteria.
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