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Traditional chemotherapy, a prevalent cancer treatment modality, is associated with significant side effects and often leads to treatment failure. Non-specific drug distribution and chemoresistance are the main factors contributing to this failure. Certain distinctive characteristics of the tumor microenvironment (TME), including hypoxia, acidic pH, and increased interstitial fluid pressure, render cancer cells resistant to conventional treatments. Multiple approaches have been devised to enhance the treatment efficiency of neoplasms and overcome chemoresistance. Nowadays, bacteria-based cancer therapy has garnered significant interest in both preclinical and clinical research, owing to its distinctive mechanism and various applications in eliciting host antitumor immunity. Due to their inherent tumor tropism, elevated motility, and capacity for quick colonization in the conducive TME, bacteria are increasingly being considered for targeted tumor treatment. Bacteria, rich in pathogen-associated molecular patterns (PAMPs), can efficiently stimulate immune cells even inside the immunosuppressive TME, boosting the particular immune detection and eradication of tumor cells. Furthermore, outer membrane vesicles (OMVs), cytoplasmic membrane vesicles (CMVs), and their derived physiological components exhibit analogous functionalities to their parental cells. This review article is representative of the latest innovations in bacteria-based immunosuppressive TME reprogramming. Additionally, the article discusses future directions in this research area, drawing on current advances. Graphical abstract Highlights Salmonella enhances the activity of CTLs and NK cells while reducing Tregs populations within the TME, thereby promoting antitumor immune responses. Listeria infects suppressive myeloid cells, boosting IL-12 and antitumor immunity. Engineered bacteria selectively colonize tumors and deliver immunostimulatory agents, reprogramming the TME to enhance antitumor immunity. Engineered OMVs act as targeted nanocarriers, accumulating in tumors and activating immune responses through PAMP delivery. Bacteria-based therapy exploits tumor hypoxia, overcoming chemo- and radio resistance.

Rumen microbiome biology gets a boost with the release of 410 high-quality reference genomes from the Hungate1000 project. Productivity of ruminant livestock depends on the rumen microbiota, which ferment indigestible plant polysaccharides into nutrients used for growth. Understanding the functions carried out by the rumen microbiota is important for reducing greenhouse gas production by ruminants and for developing biofuels from lignocellulose. We present 410 cultured bacteria and archaea, together with their reference genomes, representing every cultivated rumen-associated archaeal and bacterial family. We evaluate polysaccharide degradation, short-chain fatty acid production and methanogenesis pathways, and assign specific taxa to functions. A total of 336 organisms were present in available rumen metagenomic data sets, and 134 were present in human gut microbiome data sets. Comparison with the human microbiome revealed rumen-specific enrichment for genes encoding de novo synthesis of vitamin B 12 , ongoing evolution by gene loss and potential vertical inheritance of the rumen microbiome based on underrepresentation of markers of environmental stress. We estimate that our Hungate genome resource represents ∼75% of the genus-level bacterial and archaeal taxa present in the rumen.

Fluorinated organic chemicals, such as per- and polyfluorinated alkyl substances (PFAS) and fluorinated pesticides, are both broadly useful and unusually long-lived. To combat problems related to the accumulation of these compounds, microbial PFAS and organofluorine degradation and biosynthesis of less-fluorinated replacement chemicals are under intense study. Both efforts are undermined by the substantial toxicity of fluoride, an anion that powerfully inhibits metabolism. Microorganisms have contended with environmental mineral fluoride over evolutionary time, evolving a suite of detoxification mechanisms. In this perspective, we synthesize emerging ideas on microbial defluorination/fluorination and fluoride resistance mechanisms and identify best approaches for bioengineering new approaches for degrading and making organofluorine compounds. Microbial degradation and biosynthesis of fluorinated compounds is a field of increasing importance, but is hampered by the significant toxicity of fluoride. Here authors discuss emerging ideas on microbial defluorination/fluorination and fluoride resistance mechanisms, providing guidance on how this knowledge can guide future bioengineering approaches.

An effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines. Outer membrane vesicles (OMVs), non-replicative particles secreted by Gram-negative bacteria, are known for their immunostimulatory and adjuvant properties. Here, by employing a Plug-and-Display technology, the authors engineer OMVs to display tumor antigens on the surface, a platform that promotes anti-tumor immune responses in preclinical cancer models.

Key Points Vesicles derived from the outer membrane of Gram-negative bacteria, or outer-membrane vesicles (OMVs), are heterogeneous in size and composition, encapsulate soluble periplasmic content and are ubiquitously produced. The difficulty in finding a single molecular or genetic basis for OMV production is probably due to species-dependent differences in envelope architecture, environmental influences on envelope composition and redundancy of OMV-producing pathways. Mutations that subtly affect envelope crosslinking affect OMV production, whereas bacterial mutants that are unable to crosslink the envelope are typically unstable and form lysis products instead of OMVs. Lipopolysaccharide (LPS) subtypes also affect the levels of OMV production, as well as OMV cargo recruitment. OMV cargo may be enriched or excluded compared with its abundance in the bacterial envelope, suggesting that cargo recruitment is a regulated rather than stochastic process. Well-characterized cargoes include virulence factors, antibiotic-degrading enzymes, surface adherence factors, proteases and enzymes that are important for nutrient acquisition. OMVs can serve in bacterial communities as 'public goods' by distributing enzymes that break down extracellular material into nutrients, by recruiting iron, by acting as decoys for bacteriophages or antibiotics and by transferring DNA between cells. The versatile characteristics of OMVs and their immunomodulatory properties can be exploited for bioengineering applications and vaccine development. In this Review, Schwechheimer and Kuehn describe recent developments in elucidating the mechanisms of biogenesis and cargo selection of the outer-membrane vesicles (OMVs) produced by Gram-negative bacteria. They also discuss the functions of OMVs in bacterial physiology and during pathogenesis. Outer-membrane vesicles (OMVs) are spherical buds of the outer membrane filled with periplasmic content and are commonly produced by Gram-negative bacteria. The production of OMVs allows bacteria to interact with their environment, and OMVs have been found to mediate diverse functions, including promoting pathogenesis, enabling bacterial survival during stress conditions and regulating microbial interactions within bacterial communities. Additionally, because of this functional versatility, researchers have begun to explore OMVs as a platform for bioengineering applications. In this Review, we discuss recent advances in the study of OMVs, focusing on new insights into the mechanisms of biogenesis and the functions of these vesicles.

Multicopper oxidases (MCOs) are a pervasive family of enzymes that oxidize a wide range of phenolic and nonphenolic aromatic substrates, concomitantly with the reduction of dioxygen to water. MCOs are usually divided into two functional classes: metalloxidases and laccases. Given their broad substrate specificity and eco-friendliness (molecular oxygen from air as is used as the final electron acceptor and they only release water as byproduct), laccases are regarded as promising biological green tools for an array of applications. Among these laccases, those of bacterial origin have attracted research attention because of their notable advantages, including broad substrate spectrum, wide pH range, high thermostability, and tolerance to alkaline environments. This review aims to summarize the significant research efforts on the properties, mechanisms and structures, laccase-mediator systems, genetic engineering, immobilization, and biotechnological applications of the bacteria-source laccases and laccase-like enzymes, which principally include Bacillus laccases, actinomycetic laccases and some other species of bacterial laccases. In addition, these enzymes may offer tremendous potential for environmental and industrial applications.

Bacteriocins are potent antimicrobial peptides that are produced by bacteria. Since their discovery almost a century ago, diverse peptides have been discovered and described, and some are currently used as commercial food preservatives. Many bacteriocins exhibit extensively post-translationally modified structures encoded on complex gene clusters, whereas others have simple linear structures. The molecular structures, mechanisms of action and resistance have been determined for a number of bacteriocins, but most remain incompletely characterized. These gene-encoded peptides are amenable to bioengineering strategies and heterologous expression, enabling metagenomic mining and modification of novel antimicrobials. The ongoing global antimicrobial resistance crisis demands that novel therapeutics be developed to combat infectious pathogens. New compounds that are target-specific and compatible with the resident microbiota would be valuable alternatives to current antimicrobials. As bacteriocins can be broad or narrow spectrum in nature, they are promising tools for this purpose. However, few bacteriocins have gone beyond preclinical trials and none is currently used therapeutically in humans. In this Review, we explore the broad diversity in bacteriocin structure and function, describe identification and optimization methods and discuss the reasons behind the lack of translation beyond the laboratory of these potentially valuable antimicrobials.In this Review, Sugrue, Ross and Hill explore recent developments in bacteriocin research, including new discoveries and bioengineering approaches for improved activity, and discuss their application in microbiome modulation and clinical potential.

Lactic acid bacteria are a kind of microorganisms that can ferment carbohydrates to produce lactic acid, and are currently widely used in the fermented food industry. In recent years, with the excellent role of lactic acid bacteria in the food industry and probiotic functions, their microbial metabolic characteristics have also attracted more attention. Lactic acid bacteria can decompose macromolecular substances in food, including degradation of indigestible polysaccharides and transformation of undesirable flavor substances. Meanwhile, they can also produce a variety of products including short-chain fatty acids, amines, bacteriocins, vitamins and exopolysaccharides during metabolism. Based on the above-mentioned metabolic characteristics, lactic acid bacteria have shown a variety of expanded applications in the food industry. On the one hand, they are used to improve the flavor of fermented foods, increase the nutrition of foods, reduce harmful substances, increase shelf life, and so on. On the other hand, they can be used as probiotics to promote health in the body. This article reviews and prospects the important metabolites in the expanded application of lactic acid bacteria from the perspective of bioengineering and biotechnology.

Nisin is a bacteriocin widely utilized in more than 50 countries as a safe and natural antibacterial food preservative. It is the most extensively studied bacteriocin, having undergone decades of bioengineering with a view to improving function and physicochemical properties. The discovery of novel nisin variants with enhanced activity against clinical and foodborne pathogens has recently been described. We screened a randomized bank of nisin A producers and identified a variant with a serine to glycine change at position 29 (S29G), with enhanced efficacy against S. aureus SA113. Using a site-saturation mutagenesis approach we generated three more derivatives (S29A, S29D and S29E) with enhanced activity against a range of Gram positive drug resistant clinical, veterinary and food pathogens. In addition, a number of the nisin S29 derivatives displayed superior antimicrobial activity to nisin A when assessed against a range of Gram negative food-associated pathogens, including E. coli, Salmonella enterica serovar Typhimurium and Cronobacter sakazakii. This is the first report of derivatives of nisin, or indeed any lantibiotic, with enhanced antimicrobial activity against both Gram positive and Gram negative bacteria.

Biofilms are structured microbial communities attached to surfaces, which play a significant role in the persistence of biofoulings in both medical and industrial settings. Bacteria in biofilms are mostly embedded in a complex matrix comprised of extracellular polymeric substances that provide mechanical stability and protection against environmental adversities. Once the biofilm is matured, it becomes extremely difficult to kill bacteria or mechanically remove biofilms from solid surfaces. Therefore, interrupting the bacterial surface sensing mechanism and subsequent initial binding process of bacteria to surfaces is essential to effectively prevent biofilm-associated problems. Noting that the process of bacterial adhesion is influenced by many factors, including material surface properties, this review summarizes recent works dedicated to understanding the influences of surface charge, surface wettability, roughness, topography, stiffness, and combination of properties on bacterial adhesion. This review also highlights other factors that are often neglected in bacterial adhesion studies such as bacterial motility and the effect of hydrodynamic flow. Lastly, the present review features recent innovations in nanotechnology-based antifouling systems to engineer new concepts of antibiofilm surfaces.