Small molecule antiviral drugs have transformed the management of infections such as those caused by HIV, hepatitis B virus, hepatitis C virus, herpesviruses and influenza viruses. Effective antiviral therapeutics remain unavailable for many other often life-threatening viral infections, many of which are caused by RNA viruses. The development of potent, safe and orally available antivirals is therefore essential both to address current unmet medical needs and to strengthen epidemic and pandemic preparedness. In this Review, we discuss the rationale for building a diversified portfolio of broader-spectrum antivirals against RNA viruses with activity spanning multiple genera, entire families or even crossing viral families. We provide a non-exhaustive overview of approved and investigational antiviral agents active against RNA viruses and discuss the biological determinants that underlie their antiviral spectrum. Finally, we outline the clinical development frameworks required to accelerate the evaluation of such drugs, in particular in the context of outbreaks. In this Review, Neyts and colleagues discuss the rationale for developing broader-spectrum antivirals against RNA viruses, survey promising antiviral targets and agents, and outline strategies to accelerate clinical development and strengthen outbreak preparedness.

The instability of nitroaromatic compounds or nitroarenes in the presence of microbial cells has hindered the ability to biomanufacture these industrially and pharmaceutically relevant chemicals. Although nitroreductase (NTR) gene deletions have been linked to nitroarene stability, the extent of this effect is unclear. Here we perform a comprehensive analysis of bacterial NTR activity in cells by engineering strains of E. coli that contain up to 15 knockouts of known and candidate NTR genes. We evaluate the stability of over 20 exogenously supplemented nitroaromatic compounds to wild-type and engineered strains. For several chemistries, such as di-nitro compounds and nitro-aldehydes, our engineered nitroaromatic reductase knockout strains enable retention of compounds. We leverage these tools and insights to improve or enable nitroaromatic compound biosynthesis, including the biocatalytic transformation of an amine precursor to a nitro compound, the biosynthesis of nitrobenzaldehydes and the combined semi-synthesis and site-specific incorporation of nitrophenylalanines from supplemented nitrobenzaldehydes. This work advances access to nitro functional group chemistry in cell-based biocatalysis, metabolic engineering and synthetic biology. Nitroarenes are unstable in microbial cultures, limiting the biomanufacturing of these industrially and pharmaceutically important chemicals. Genome engineering of nitroreductase-deficient E. coli strains has now been shown to improve nitroarene retention during fermentation, expanding access to nitro functional group chemistry in whole-cell biocatalysis, metabolic engineering and synthetic biology.

Nitrogen (N) fertilizers are key drivers of high yields in rice (Oryza sativa L.), yet increasing N inputs often deliver diminishing improvements in N use efficiency (NUE) and can exacerbate N losses via volatilization, leaching, and runoffs, with associated environmental impacts. The rice phyllosphere microbiome, which consists of microbes inhabiting leaf surfaces and internal tissues, has the potential to influence foliar nutrient turnover, N metabolism, and stress responses and may therefore influence internal NUE (IEN) and, under reduced fertilizer-N input, potentially affect agronomic efficiency of applied N (AEN). Here, we summarize the major steps of rice N metabolism (uptake, assimilation, transport, redistribution, and remobilization) and discuss microbial pathways that could modulate N use, including foliar N transformations, microbially mediated N inputs, and indirect effects through hormonal regulation, stress buffering, and microbe–microbe interactions. Key knowledge gaps remain in quantification of underlying mechanistic processes, field robustness across seasons and sites, and genotype/microbiome matching under reduced-N management.

Bacterial extracellular vesicles (BEVs) are nanosized membrane-bound nanoparticles naturally secreted by Gram-negative and Gram-positive bacteria. These vesicles mediate intercellular communication through delivery of diverse bioactive cargo, including proteins, lipids, nucleic acids, metabolites, and signaling molecules. Initially recognized as virulence determinants in pathogenic bacteria, BEVs are increasingly recognized as multifunctional platforms with potential applications in sustainable agriculture. This review examines BEV biogenesis, cargo composition, plant uptake, and emerging roles in plant growth promotion, stress adaptation, and disease resistance. Emphasis is placed on BEV-mediated modulation of plant immunity through pattern recognition receptors (PRRs), pattern-triggered immunity (PTI), and induced systemic resistance (ISR). Potential roles of vesicle-associated phytohormones, ACC deaminase, siderophores, extracellular enzymes, and regulatory RNAs in nutrient acquisition, phytohormone homeostasis, and stress responses are critically evaluated. Emerging evidence linking BEVs to drought, salinity, heat, heavy metal, and nutrient-deficiency responses is examined, with emphasis on antioxidant defense, osmotic adjustment, ion homeostasis, and stress-responsive signaling. The review also discusses engineered BEVs as potential biostimulants, nano-biofertilizers, biocontrol agents, and precision delivery systems, including CRISPR-based engineering, synthetic vesicles, AI-guided cargo optimization, and smart nanoformulations. Major challenges include scalable production, standardization, biosafety, regulation, and field validation. However, critical knowledge gaps remain regarding BEV perception, cellular uptake, cargo delivery, and the causal basis of plant responses, together with uncertainties surrounding biosafety, reproducibility, and performance under field conditions. Collectively, BEVs represent promising biological nanocarriers for climate-resilient and sustainable agriculture, but further mechanistic, methodological, and field-based research is required to establish their reliability and practical agricultural potential. Graphical abstract

The failure of antibiotic treatment is a growing concern, driven in large part by the rising incidence of antimicrobial resistance (AMR). Increasing evidence points to the importance of microbial competition in preventing the colonization of disease-causing pathogens and the spread of AMR. Crucially, the pathogens we target with antibiotics do not exist in isolation but instead compete and interact with the microbial communities that colonize the human body, microbiomes. Here, we therefore argue that the key to approaching the challenge of antibiotic treatment failure is understanding the strategies and mechanisms that microbes use to succeed in microbiomes. We discuss how microbial competition influences the colonization of pathogens and the spread of resistance via horizontal gene transfer. We then discuss how microbial competition may be used to synergize with antibiotic treatment or even replace it. Overall, we argue that studying microbial interactions offers a powerful approach to understanding and even mitigating antibiotic treatment failure.

The gut microbiota plays a pivotal part in human health, yet the molecular mechanisms that underlie its effects are largely unexplored. Bacteroides, a dominant genus in the human gut microbiota, is depleted in patients with atherosclerosis, but its causal relationship with disease remains unclear. Here, using a mouse model, we show that administration of Bacteroides uniformis alleviates atherosclerosis through the upregulation of hepatic low-density lipoprotein receptor expression. Bioactivity-guided screening revealed pentadecanoic acid (PA, C15:0), a saturated odd-chain fatty acid, as a principal bioactive metabolite. PA supplementation reduced  atherosclerotic plaque burden by around 50% and significantly improved plasma lipid profiles, a result that underscores its therapeutic potential. Mechanistically, PA enhances cholesterol clearance by directly inhibiting HMG-CoA reductase, suppressing hepatic cholesterol biosynthesis and promoting plasma low-density lipoprotein cholesterol removal. Analyses of 100 gut bacterial strains revealed that PA production occurs across multiple Bacteroidota genera. Notably, PA is markedly depleted in patients with dyslipidaemia. In summary, a Bacteroidota-derived odd-chain fatty acid regulates gut–liver crosstalk, and modulation of the microbial–metabolic axis has atheroprotective potential. The administration of Bacteroides uniformis in mice can mitigate atherosclerosis via pentadecanoic acid, which directly inhibits HMG-CoA reductase to promote hepatic cholesterol clearance.

Antibiotic resistance has emerged as a major bottleneck in antibiotic development, frequently undermining promising drug candidates and negating years of research and pharmaceutical investment. Despite growing recognition of this issue, discovery pipelines still emphasize potency and target specificity whereas resistance potential is often considered later in the development process. Predicting resistance remains challenging owing to the diversity of genetic mechanisms, species-specific adaptive pathways and potential side effects of resistance on bacterial viability. However, technological advances now enable systematic mapping of resistance evolution, the dissemination of resistance genes and prediction of the clinical impact. To improve early identification of resistance-prone antibiotic candidates, it is crucial to evaluate five key parameters, including de novo resistance evolvability across pathogens, resistance–fitness–virulence trade-offs, resistance stability, cross-resistance potential and health risk of resistance genes. Integrating these factors provides a systematic, resistance-based framework for classifying new antibiotic candidates and guiding compound prioritization and refinement. Utilizing this framework within the antibiotic development pipeline shifts resistance prediction from retrospective observation to a prospective guiding principle in drug design. Resistance emergence is a major challenge to antibiotic development, often undermining promising drug candidates and negating years of research and pharmaceutical investment. In this Review, Pál and colleagues propose a resistance-based classification system for antibiotic development that integrates early resistance predictions into the prospective development of new antibiotics.

The E. coli chromosomal origin, oriC, contains a duplex-unwinding element (DUE) flanked by two clusters of the initiator DnaA-binding sites (DnaA boxes). ATP-DnaA oligomerizes to construct Left- and Right–DnaA subcomplexes on these clusters. These complexes coordinately promote DUE unwinding and DnaB helicase loading onto the unwound region for replication initiation. However, despite the strong conservation of DnaA and DnaB across bacterial species, oriC architectures vary largely. Remarkably, bipartite and bilateral configurations contain the two DnaA box-clusters separated by an insertion of the dnaA gene or positioned on both sides of the DUE, respectively. Here, we demonstrate that E. coli oriC variants mimicking these configurations remain fundamentally functional. Notably, DnaB loading activity of these variants showed increased dependence on single-stranded DUE binding by the relocated DnaA subcomplex and on the AT cluster upstream of the DUE, reflecting reduced stability of DUE unwinding. Consistent with these in vitro results, these variants supported cellular replication initiation with only slow cell growth rates. Together, these findings reveal remarkable architectural flexibility, mechanistic robustness, and a conserved mechanism in oriC. Also, those highlight unwinding stability as a key determinant of oriC adaptation to rapid cell growth, providing insight into the evolution of oriC architecture.

The rational engineering of non-model microorganisms is often constrained by the scarcity of high-performance genetic regulatory tools. To overcome this limitation, we developed ARCANE – a reprogrammable circuit architecture for non-model engineering – featuring a cascaded design in which an inducer controls orthogonal bacterial transcription factors (bTFs), which in turn drive both activation and repression of endogenous promoters. This architecture provides strong insulation from host regulatory networks, minimizes leakage, and enables a broad dynamic range. As a proof-of-concept, we implemented ARCANE in the industrially significant non-model yeast, Yarrowia lipolytica. The resulting genetic switch exhibited exceptionally precise and tunable control over both single reporter genes and a multi-gene carotenoid biosynthesis pathway. Beyond providing a powerful regulatory tool for Y. lipolytica, ARCANE offers a versatile and transferable modular foundation for programmable gene control in emerging microbial platforms, paving the way for scalable synthetic biology in non-model systems.