Clinical crusade: zosurabalpin's charge against antibiotic resistance.

In a recent report, Zampaloni et al. describe a novel tethered macrocyclic peptide (MCP) antibiotic, zosurabalpin, that disrupts the essential function of the LptB2FGC complex in Gram-negative bacteria and demonstrates efficacy against carbapenem-resistant Acinetobacter baumannii (CRAB). Its preclinical success suggests a substantial shift in treating antibiotic resistance, pending clinical trials to validate its effectiveness, pharmacokinetics, and resistance management.

Biosafety and biosecurity: treading China's synbio tightrope.

Our second piece dissects China's intricate balancing act in synthetic biology (synbio), analyzing its adept maneuvering between fostering innovation and imposing strict regulations. The priority is enhancing biosecurity, biosafety, and public trust, crucial for sustainable gene editing advancements and preventing potential misuse of synthetic viruses.

The gut-Snhg9 interplay as a new path to metabolic health.

Parsing the intricate interplay between gut microbiota, gene modulation, and host metabolism remains challenging. Wang et al. employed diverse methods to uncover how the gut microbiota reshapes intestinal lipid metabolism through the lncRNA Snhg9, underscoring the value of systems biology approaches in dissecting host-microbiome relationships involved in metabolic disorders.

Genomics refined: AI-powered perspectives on structural analysis.

Understanding protein function by deciphering 3D structure has distinct limitations. A recent study by Huang et al. used AlphaFold2, an artificial intelligence (AI) protein-folding prediction model, to predict and classify deaminase proteins based on structural similarities, highlighting the untapped potential of AI in functional genomics and protein engineering.

Intellectual property and funding: fueling Chinese synbio.

As China emerges as a synthetic biology (synbio) global leader, it faces distinct science-society challenges. Our series offers a snapshot of China's synbio state, emphasizing the intersection and its policy implications. The debut piece elucidates the intellectual property rights (IPR)-funding interplay in China's expanding synbio territory, underlining its key role in driving innovation and commercialization.

Microbial gatekeepers: unraveling the role of the gut microbiota enzyme DPP4 in diabetes management.

Wang et al. identified dipeptidyl peptidase 4 (DPP4) as a gut microbe-derived enzyme that impacts on host glucose metabolism. They further introduced a novel therapeutic, daurisoline-d4 (Dau-d4), a selective microbial DPP4 (mDPP4) inhibitor that shows promise in improving glucose tolerance, highlighting the potential of therapies that target both host enzymes and gut microbial enzymes.

Exploring the antibiotic potential of cultured 'unculturable' bacteria.

In response to the severe global antibiotic resistance crisis, this forum delves into 'unculturable' bacteria, believed to be a promising source of novel antibiotics. We propose remarkable drug discovery strategies that leverage these bacteria's diversity, aspiring to transform resistance management. The urgent call for new antibiotics accentuates the essentiality of further research.

Ethics and engagement: steering China's synbio future.

In the final article of the series, we delve into the crucial role of public engagement and ethical guidelines in shaping the trajectory of synthetic biology (synbio) within China's evolving scientific landscape. We discuss the interconnectedness of enhanced public discourse, stronger ethics, and responsible, transparent advancements in the field.

Redefining the Glyphosate Sector: Harmonizing Inventiveness and Sustainable Practices for a Better World.

The glyphosate industry has long been a critical player in global agriculture, providing effective and economical solutions for weed control. However, growing concerns over environmental and health impacts have led to increased scrutiny and calls for more sustainable practices. This Viewpoint focuses on the scientific aspects of greener glyphosate synthesis strategies, discussing recent advancements in biobased pathways and catalytic methods, challenges such as scalability and technical hurdles, and future prospects for the herbicide industry. By embracing these new techniques, we can ensure a more sustainable future for herbicide production and contribute to a healthier world.

Discovery and biosynthesis of tricyclic copper-binding ribosomal peptides containing histidine-to-butyrine crosslinks.

Cyclic peptide natural products represent an important class of bioactive compounds and clinical drugs. Enzymatic side-chain macrocyclization of ribosomal peptides is a major strategy developed by nature to generate these chemotypes, as exemplified by the superfamily of ribosomally synthesized and post-translational modified peptides. Despite the diverse types of side-chain crosslinks in this superfamily, the participation of histidine residues is rare. Herein, we report the discovery and biosynthesis of bacteria-derived tricyclic lanthipeptide noursin, which is constrained by a tri amino acid labionin crosslink and an unprecedented histidine-to-butyrine crosslink, named histidinobutyrine. Noursin displays copper-binding ability that requires the histidinobutyrine crosslink and represents the first copper-binding lanthipeptide. A subgroup of lanthipeptide synthetases, named LanKCHbt, were identified to catalyze the formation of both the labionin and the histidinobutyrine crosslinks in precursor peptides and produce noursin-like compounds. The discovery of the histidinobutyrine-containing lanthipeptides expands the scope of post-translational modifications, structural diversity and bioactivity of ribosomally synthesized and post-translational modified peptides.

Concise Biosynthesis of Tropone-Containing Spiromaterpenes by a Sesquiterpene Cyclase and a Multifunctional P450 from a Deep-Sea-Derived Spiromastix sp. Fungus.

Spiromaterpenes are a group of rare tropone-containing sesquiterpenes with antineuroinflammatory activity. Herein, we elucidate their biosynthetic pathway in a deep-sea-derived Spiromastix sp. fungus by heterologous expression, biochemical characterization, and incubation experiments. The sesquiterpene cyclase SptA was first characterized to catalyze the production of guaia-1(5),6-diene, and a multifunctional cytochrome P450 catalyzed the tropone ring formation. These results provide important clues for the rational mining of bioactive guaiane-type sesquiterpenes and expand the repertoire of P450 activities to synthesize unique building blocks of natural products.

Hijacking a Linaridin Biosynthetic Intermediate for Lanthipeptide Production.

Linaridins and lanthipeptides are two classes of natural products belonging to the ribosomally synthesized and posttranslationally modified peptide (RiPP) superfamily. Although these two RiPP classes share similar structural motifs such as dehydroamino acids and thioether-based cross-links, the biosynthesis of linaridins and lanthipeptides involved distinct sets of enzymes. Here, we report the identification of a novel lanthipeptide cypepeptin from a recombinant strain of Streptomyces lividans, which harbors most of the cypemycin (a prototypic linaridin) biosynthetic gene cluster but lacks the decarboxylase gene cypD. In contrast to the generally believed structure of cypemycin, multiple d-amino acids and Z-dehydrobutyrines were observed in both cypepeptin and cypemycin, and the stereochemistry of each amino acid was established by the extensive structural analysis in combination with genetic knockout and mutagenesis studies. Comparative analysis of cypemycin and cypepeptin showed that the aminovinyl-cysteine (AviCys) moiety of cypemycin plays an essential role in disrupting the cell integrity of M. luteus, which cannot be functionally substituted by the structurally similar lanthionine moiety.

Harnessing phosphonate antibiotics argolaphos biosynthesis enables a synthetic biology-based green synthesis of glyphosate.

Glyphosate is a widely used herbicide with an annual production of more than one million tons globally. Current commercialized production processes of glyphosate are generally associated with manufacturing hazards and toxic wastes. Recently, many countries have strengthened environmental supervision and law enforcement on glyphosate manufacturing. Therefore, a green source of glyphosate is required. Here, we characterize the genes required for producing aminomethylphosphonate (AMP), one of the intermediates in the biosynthesis of the potent antibiotics argolaphos. We apply a synthetic biology strategy to improve AMP production in Streptomyces lividans, with fermentation titers of 52 mg L-1, a 500-fold improvement over the original strain. Furthermore, we develop an efficient and practical chemical process for converting AMP to glyphosate. Our findings highlight one greenness-driven alternative in the production of glyphosate.

Heterologous expression and characterization of glycoside hydrolase with its potential applications in hyperthermic environment.

With the progressive focus on renewable energy via biofuels production from lignocellulosic biomass, cellulases are the key enzymes that play a fundamental role in this regard. This study aims to unravel the characteristics of Thermotoga maritima MSB8 (Tma) (a hyperthermophile from hot springs) thermostable glycoside hydrolase enzyme. Here, a glycoside hydrolase gene of Thermotoga maritima (Tma) was heterologously expressed and characterized. The gene was placed in the pQE-30 expression vector under the T5 promotor, and the construct pQE-30-Gh was then successfully integrated into Escherichia coli BL21 (DH5α) genome by transformation. Sequence of the glycoside hydrolase contained an open reading frame of 2.124 kbp, encoded a polypeptide of 721 amino acid residues. The molecular weight of the recombinant protein estimated was 79 kDa. The glycoside hydrolase was purified by Ni+2-NTA affinity chromatography and its enzymatic activity was investigated. The recombinant enzyme is highly stable within an extreme pH range (2.0-7.0) and highly thermostable at 80 °C for 72 h indicating its viability in hyperthermic environment and acidic nature. Moreover, the Ca2+ and Mn2+ introduction stimulated the residual activity of recombinant enzyme. Conclusively, the thermostable glycoside hydrolase possesses potential to be exploited for industrial applications at hyperthermic environment.

Effective removal of the herbicide glyphosate by the kelp Saccharina japonica female gametophytes from saline waters and its mechanism elucidation.

Glyphosate has been widely and extensively used for weed control because of its excellent herbicidal profile and low costs. However, more than 750 glyphosate products are on the market and are increasingly regarded as water pollutants as they cause adverse effects on aquatic life. Dry cell weight and photosynthesis of Saccharina japonica female gametophytes increased when glyphosate was used as the sole phosphorus source at the concentration of less than 20 mg L-1. Nuclear magnetic resonance (NMR) analysis unambiguously confirmed that female gametophytes of the brown alga Saccharina japonica have the capability of breaking the C-P bond of glyphosate to orthophosphate, which finds the enormous potential of the most common seaweed to degrade the most widely used herbicide in the world. Furthermore, this is the first report on the use of glyphosate as the sole phosphorus source for the growth of eukaryotic cells. Because of the wide distribution and relatively easy cultivation of the fast-growing brown alga Saccharina japonica on the coast, our results set a promising stage for developing large macroalgae-based biotechnologies that can be applied for the remediation of contaminated seawater, which is greener and more cost-effective than conventional treatment methods.

Genome mining as a biotechnological tool for the discovery of novel marine natural products.

Compared to terrestrial environments, the oceans harbor a variety of environments, creating higher biodiversity, which gives marine natural products a high occurrence of significant biology and novel chemistry. However, traditional bioassay-guided isolation and purification strategies are severely limiting the discovery of additional novel natural products from the ocean. With an increasing number of marine microorganisms being sequenced, genome mining is gradually becoming a powerful tool to retrieve novel marine natural products. In this review, we have summarized genome mining approaches used to analyze key enzymes of biosynthetic pathways and predict the chemical structure of new gene clusters by introducing successful stories that used genome mining strategy to identify new marine-derived compounds. Furthermore, we also put forward challenges for genome mining techniques and their proposed solutions. The detailed analysis of the genome mining strategy will help researchers to understand this novel technique and its application. With the development of a genome sequence, genome mining strategies will be applied more widely, which will drive rapid development in the field of marine natural product development.

C-P Natural Products as Next-Generation Herbicides: Chemistry and Biology of Glufosinate.

In modern agriculture and weed management practices, herbicides have been widely used to control weeds effectively and represent more than 50% of commercial pesticides applied in the world. Herbicides with unique mechanisms of actions (MOA) have historically been discovered and commercialized every two or three years from the 1950s to the 1980s. However, this trend lowered dramatically as no herbicide with a novel MOA has been marketed for more than 30 years. The fast-growing resistance to commercial herbicides has reignited the agricultural chemical industry interest in new structural scaffolds targeting novel sites in plants. Carbon-phosphorus bonds (C-P) containing natural products (NPs) have played an essential role in herbicide discovery as the chemical diversity, and the promising bioactivity of natural C-P phytotoxins can provide exciting opportunities for the discovery of both natural and semisynthetic herbicides with novel targets. Among commercial herbicides, glyphosate (Roundup), a famous C-P containing herbicide, is by far the most universally used herbicide worldwide. Furthermore, glufosinate is one of the most widely used natural herbicides in the world. Therefore, C-P NPs are a treasure for discovering new herbicides with novel mechanisms of actions (MOAs). Here, we present an overview of the chemistry and biology of glufosinate including isolation and characterization, mode of action, herbicidal use, biosynthesis, and chemical synthesis since its discovery in order to not only help scientists reassess the role of this famous herbicide in the field of agrichemical chemistry but also build a new stage for discovering novel C-P herbicides with new MOAs.

Discovery of Three New Phytotoxins from the Fungus Aspergillus nidulans by Pathway Inactivation.

Fungi are a source of novel phytotoxic compounds to be explored in the search for effective and environmentally safe herbicides. The genetic inactivation of the biosynthetic pathway of the new phytotoxin cichorine has led to the isolation of three novel phytotoxins from the fungus Aspergillus nidulans: 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6). The structure of the new compounds was clearly determined by a combination of nuclear magnetic resonance (NMR) analysis and high-resolution electrospray ionization (HRESIMS). The phytotoxic bioassay was studied on leaves from Zea mays and Medicago polymorpha L. at the concentration of 5 × 10-3 M by using a moist chamber technique. Novel phytotoxins 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6) exhibited a better phytotoxic effect than cichorine.

Effects of cpxR on the growth characteristics and antibiotic production of Xenorhabdus nematophila.

CpxR is a global response regulator that negatively influences the antimicrobial activities of Xenorhabdus nematophila. Herein, the wildtype and ΔcpxR mutant of X. nematophila were cultured in a 5-l and 70-l bioreactor. The kinetic analysis showed that ΔcpxR significantly increased the cell biomass and antibiotic activity. The maximum dry cell weight (DCW) and antibiotic activity of ΔcpxR were 20.77 ± 1.56 g L-1 and 492.0 ± 31.2 U ml-1 and increased by 17.28 and 97.33% compared to the wildtype respectively. Xenocoumacin 1 (Xcn1), a major antimicrobial compound, was increased 3.07-fold, but nematophin was decreased by 48.7%. In 70-l bioreactor, DCW was increased by 18.97%, while antibiotic activity and Xcn1 were decreased by 27.71% and 11.0% compared to that in 5-l bioreactor respectively. Notably, pH had remarkable effects on the cell biomass and antibiotic activity of ΔcpxR, where ΔcpxR was sensitive to alkaline pH conditions. The optimal cell growth and antibiotic activity of ΔcpxR occurred at pH 7.0, while Xcn1 was increased 5.45- and 3.87-fold relative to that at pH 5.5 and 8.5 respectively. These findings confirmed that ΔcpxR considerably increased the biomass of X. nematophila at a late stage of fermentation. In addition, ΔcpxR significantly promoted the biosynthesis of Xcns but decreased the production of nematophin.

The intriguing biology and chemistry of fosfomycin: the only marketed phosphonate antibiotic.

Recently infectious diseases caused by the increased emergence and rapid spread of drug-resistant bacterial isolates have been one of the main threats to global public health because of a marked surge in both morbidity and mortality. The only phosphonate antibiotic in the clinic, fosfomycin, is a small broad-spectrum molecule that effectively inhibits the initial step in peptidoglycan biosynthesis by blocking the enzyme, MurA in both Gram-positive and Gram-negative bacteria. As fosfomycin has a novel mechanism of action, low toxicity, a broad spectrum of antibacterial activity, excellent pharmacodynamic/pharmacokinetic properties, and good bioavailability, it has been approved for clinical use in the treatment of urinary tract bacterial infections in many countries for several decades. Furthermore, its potential use for difficult-to-treat bacterial infections has become promising, and fosfomycin has become an ideal candidate for the effective treatment of bacterial infections caused by multidrug-resistant isolates, especially in combination with other therapeutic drugs. Here we aim to present an overview of the biology and chemistry of fosfomycin including isolation and characterization, pharmacology, biosynthesis and chemical synthesis since its discovery in order to not only help scientists reassess the role of this exciting drug in fighting antibiotic resistance but also build the stage for discovering more novel phosphonate antibiotics in the future.