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Abstract Antibody–drug conjugates (ADCs) have gained significant attention in biotherapeutics after several years of steady development. Among the multiple factors influencing ADC design, the conjugation method is one of the most critical parameters. This review classifies conjugation strategies into three categories: non-specific, site-specific but non-selective, and fully site-specific and selective methods. The characteristics; advantages and disadvantages; chemistry, manufacturing, and controls (CMC) potential; and clinical status of each conjugation strategy are discussed in detail. The site-specific and selective methods will yield more homogeneous ADC, which may influence the stability and pharmacokinetics (PK) profile of the ADC and then influence the final therapeutic outcome. Additionally, the review also explores challenges and future directions for developing novel conjugation strategies. This review presents the most prevalent conjugation techniques, providing a valuable resource for researchers in selecting conjugation technologies and advancing ADC development. This review presents the most prevalent conjugation techniques used in clinical ADC pipelines or those with significant potential; compares the characteristics, advantages and shortcomings, CMC potential, and clinical status of each conjugation strategy; and discusses the potential challenges for further development of novel conjugation strategies.

Bacterial conjugation is one of the main mechanisms for horizontal gene transfer. It constitutes a key element in the dissemination of antibiotic resistance and virulence genes to human pathogenic bacteria. DNA transfer is mediated by a membrane-associated macromolecular machinery called Type IV secretion system (T4SS). T4SSs are involved not only in bacterial conjugation but also in the transport of virulence factors by pathogenic bacteria. Thus, the search for specific inhibitors of different T4SS components opens a novel approach to restrict plasmid dissemination. This review highlights recent biochemical and structural findings that shed new light on the molecular mechanisms of DNA and protein transport by T4SS. Based on these data, a model for pilus biogenesis and substrate transfer in conjugative systems is proposed. This model provides a renewed view of the mechanism that might help to envisage new strategies to curb the threating expansion of antibiotic resistance. Bacterial conjugation is one of the main mechanisms for the dissemination of antibiotic resistance genes. Here, we suggest a model that integrates the mechanism of conjugation with Type IV secretions systems biogenesis and substrate transport across the secretion channel and we propose alternative approaches to use this knowledge in the fight against the spread of antibiotic resistance.

Invited for this month′s cover is the group of Jean‐Paul Desaulniers at Ontario Tech University. The cover picture shows the successful conjugation of a GaIII‐corrole to an siRNA to enable live cell imaging. Read the full text of the article at 10.1002/cplu.202400084. “The biggest surprise was not obtaining the triple therapeutic effect… that we would have expected with the introduction of GaIII‐corrole to the siRNA.” This and more about the story behind the front cover can be found in the article at 10.1002/cplu.202400084).

Photoluminescence (PL) mechanisms of nontraditional luminogens (NTLs) have attracted great interest, and they are generally explained with intra/intermolecular through‐space conjugation (TSC) of nonconventional chromophores. Here a new concept of nonaromatic through‐bond conjugation (TBC) is proposed and it is proved that it plays an important role in the PL of NTLs. The PL behaviors of the three respective isomers of cyclohexanedione and gemdimethyl‐1,3‐cyclohexanedione were studied and correlated with their chemical and aggregate structures. These compounds show different fluorescence emissions as well as different concentration, excitation and solvent‐dependent emissions. The compounds which undergo keto‐enol tautomerism and hence with a conjugated ketone‐enol structure (i.e., nonaromatic TBC) show more red‐shifted emissions. TBC effect reduces the energy gaps and facilitates the formation of stronger TSC in the aggregate state. The compounds in the ketone‐enol form are also prone to occur excited state intra/intermolecular proton transfer (ESIPT). The cooperative effect of nonaromatic TBC and TSC determines the PL behaviors of NTLs. This work provides a novel understanding of the PL mechanisms of NTLs and is of great importance for directing the design and synthesis of novel NTLs. A novel concept of nonaromatic through‐bond conjugation (TBC) is proposed and it is proven to play an important role in the photoluminescence of nontraditional luminogens by studying the relationship between the photophysical properties of the isomers of cyclohexanedione and dimethyl‐1,3‐cyclohexanedione and their chemical structures, aggregate structures and interactions.

Antibiotic resistance threatens our ability to treat infectious diseases, spurring interest in alternative antimicrobial technologies. The use of bacterial conjugation to deliver CRISPR‐ cas systems programmed to precisely eliminate antibiotic‐resistant bacteria represents a promising approach but requires high in situ DNA transfer rates. We have optimized the transfer efficiency of conjugative plasmid TP114 using accelerated laboratory evolution. We hence generated a potent conjugative delivery vehicle for CRISPR‐ cas9 that can eliminate > 99.9% of targeted antibiotic‐resistant Escherichia coli in the mouse gut microbiota using a single dose. We then applied this system to a Citrobacter rodentium infection model, achieving full clearance within four consecutive days of treatment. SYNOPSIS A conjugative plasmid with high transfer rates is leveraged to deliver the CRISPR system into targeted bacteria. The resulting conjugative system can clear a C. rodentium infection in mice. Conjugative plasmid TP114 can be used for the delivery of CRISPR‐Cas systems by an engineered conjugative probiotic (COP) strain. Accelerated laboratory evolution was conducted to further increase TP114 transfer rates in the gut microbiota. The COP approach was able to knock down antibiotic‐resistant bacteria from a probed population in situ . The improved eB‐COP system enabled the complete clearance of a C. rodentium infection in mice with similar efficiency as a conventional antibiotic treatment. Graphical Abstract A conjugative plasmid with high transfer rates is leveraged to deliver the CRISPR system into targeted bacteria. The resulting conjugative system can clear a C. rodentium infection in mice.

This article introduces two novel A-D-A type small molecules. Compared to traditional methylene-based dye materials, these compounds exhibit enhanced conjugation and improved stability. The newly studied A-D-A type small molecules in this research possess narrow bandgaps, broad absorption in the visible light range, strong fluorescence, and good solubility.

Bacterial conjugation systems are members of the large type IV secretion system (T4SS) superfamily. Conjugative transfer of F plasmids residing in the Enterobacteriaceae was first reported in the 1940s, yet the architecture of F plasmid-encoded transfer channel and its physical relationship with the F pilus remain unknown. We visualized F-encoded structures in the native bacterial cell envelope by in situ cryoelectron tomography (CryoET). Remarkably, F plasmids encode four distinct structures, not just the translocation channel or channel-pilus complex predicted by prevailing models. The F1 structure is composed of distinct outer and inner membrane complexes and a connecting cylinder that together house the envelope-spanning translocation channel. The F2 structure is essentially the F1 complex with the F pilus attached at the outer membrane (OM). Remarkably, the F3 structure consists of the F pilus attached to a thin, cell envelope-spanning stalk, whereas the F4 structure consists of the pilus docked to the OM without an associated periplasmic density. The traffic ATPase TraC is configured as a hexamer of dimers at the cytoplasmic faces of the F1 and F2 structures, where it respectively regulates substrate transfer and F pilus biogenesis. Together, our findings present architectural renderings of the DNA conjugation or “mating” channel, the channel–pilus connection, and unprecedented pilus basal structures. These structural snapshots support a model for biogenesis of the F transfer system and allow for detailed comparisons with other structurally characterized T4SSs.

The Front Cover represents the successful conjugation of a GaIII‐corrole to a siRNA, thereby enabling live‐cell imaging. Both HeLa cells imaged with the GaIII‐corrole and the structure of the GaIII‐corrole‐siRNA are shown in yellow and purple. The central image is an illustration of a camera lens, showing the three important components used to produce the live imaging results (GaIII‐corrole‐siRNA, microscope, and HeLa cells). More information can be found in the Research Article by J.‐P. Desaulniers and co‐workers. Cover design by I.G.

When an electromagnetic (EM) wave propagates in a medium whose properties are varied abruptly in time, the wave experiences refractions and reflections known as time-refractions and time-reflections, both manifesting spectral translation as a consequence of the abrupt change of the medium and the conservation of momentum. However, while the time-refracted wave continues to propagate with the same wave-vector, the time-reflected wave propagates backward with a conjugate phase despite the lack of any spatial interface. Importantly, while time-refraction is always significant, observing time-reflection poses a major challenge – because it requires a large change in the medium occurring within a single cycle of the EM wave. For that reason, time-reflection of EM waves was observed only recently. Here, we present the observation of microwave pulses at the highest frequency ever observed (0.59 GHz), and the experimental evidence of the phase-conjugation nature of time-reflected waves. Our experiments are carried out in a periodically-loaded microstrip line with optically-controlled picosecond-switchable photodiodes. Our system paves the way to the experimental realization of Photonic Time-Crystals at GHz frequencies. Time-reflected waves are a critical feature of time-crystals, yet their properties are historically difficult to measure. Here, the authors experimentally demonstrate time-reflected electromagnetic waves including direct evidence of their phase conjugate nature.