Harnessing Endogenous Formate for Antibacterial Prodrug Activation by in cellulo Ruthenium‐Mediated Transfer Hydrogenation Reaction

The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination‐directed 3‐component assembly to prepare a library of 768 unique Ru–Arene Schiff‐base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites.     

Black Phosphorus Nanosheets Counteract Bacteria without Causing Antibiotic Resistance

Antibiotic resistance poses severe health threats throughout the world. Exploring new antibiotics is widely recognized as an effective strategy to counter antibiotic resistance, but new antibiotics will eventually lead to further antibiotic resistance when new drugs are misused or overused. An alternative tactic may be antibacterial regulation on demand. Here, we show experimentally and theoretically that unstable black phosphorus nanosheets (BPNs) can function as antibacterial agents without causing antibiotic resistance. This antibacterial strategy relies on an unprecedented synergism: The BPNs use reactive oxygen species, are not toxic towards nonbacterial cells within a wide range of BPN concentration (0.01–2.0 mg mL⁻¹), and are chemically degradable on demand. BPNs thus offer a promising approach to fighting bacterial infections without causing antibiotic resistance. We believe this proposed strategy offers new insights into instability-guided antibacterial therapy in clinical applications and indicates a new direction for fighting antibiotic resistance.     

Cyclization-activated prodrugs

Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter- and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990 s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.     

Multifunctional fibrous wound dressings for refractory wound healing

Refractory wounds have always been an important issue to healthcare systems, whose healing process is always delayed by multiple factors, including bacterial infections, chronic inflammation, and excessive exudates, etc. Employing multifunctional wound dressings is recognized as an effective strategy to deal with refractory wounds, which has yielded promising outcomes in recent years. Among these advanced wound dressings, fibrous dressings have gained growing attention due to their unique merits. Such wound dressings have demonstrated great potential in delivering theranostic agents, such as antibacterial agents, anti-inflammatory drugs, growth factors, and diagnostic probes, etc., for the purposes of accelerating wound healing. This paper reviews the development of multifunctional fibrous dressings and their applications in treating refractory wounds. The construction approaches of novel fibrous dressing with capabilities of antibacterial, anti-inflammation, exudate management and diagnosis were also introduced. Furthermore, the existing problems and challenges are also discussed briefly.     

Jointly handling potency and toxicity of antimicrobial peptidomimetics by simple rules from desirability theory and chemoinformatics

Today, emerging and increasing resistance to antibiotics has become a threat to public health worldwide. Antimicrobial peptides have unique action mechanisms making them an attractive therapeutic prospect to be applied against resistant bacteria. However, the major drawback is related with their high hemolytic activity which cancels out the safety requirements for a human antibiotic. Therefore, additional efforts are needed to develop new antimicrobial peptides that possess a greater potency for bacterial cells and less or no toxicity over erythrocytes. In this paper, we introduce a practical approach to simultaneously deal with these two conflicting properties. The convergence of machine learning techniques and desirability theory allowed us to derive a simple, predictive, and interpretable multicriteria classification rule for simultaneously handling the antibacterial and hemolytic properties of a set of cyclic β-hairpin cationic peptidomimetics (Cβ-HCPs). The multicriteria classification rule exhibited a prediction accuracy of about 80% on training and external validation sets. Results from an additional concordance test have shown an excellent agreement between the multicriteria classification rule predictions and the predictions from independent classifiers for complementary antibacterial and hemolytic activities, respectively, evidencing the reliability of the multicriteria classification rule. The rule was also consistent with the general mode of action of cationic peptides pointing out its biophysical relevance. We also propose a multicriteria virtual screening strategy based on the joint use of the multicriteria classification rule, desirability, similarity, and chemometrics concepts. The ability of such a virtual screening strategy to prioritize selective (nonhemolytic) antibacterial Cβ-HCPs was assessed and challenged for their predictivity regarding the training, validation, and overall data. In doing so, we were able to rank a selective antibacterial Cβ-HCP earlier than a biologically inactive or nonselective antibacterial Cβ-HCP with a probability of ca. 0.9. Our results thus indicate that promising chemoinformatics tools were obtained by considering both the multicriteria classification rule and the virtual screening strategy, which could, for instance, be used to aid the discovery and development of potent and nontoxic antimicrobial peptides.     

A Supramolecular Antibiotic Switch for Antibacterial Regulation

A supramolecular antibiotic switch is described that can reversibly “turn‐on” and “turn‐off” its antibacterial activity on demand, providing a proof‐of‐concept for a way to regulate antibacterial activity of biotics. The switch relies on supramolecular assembly and disassembly of cationic poly(phenylene vinylene) derivative (PPV) with cucurbit[7]uril (CB[7]) to regulate their different interactions with bacteria. This simple but efficient strategy does not require any chemical modification on the active sites of the antibacterial agent, and could also regulate the antibacterial activity of classical antibiotics or photosensitizers in photodynamic therapy. This supramolecular antibiotic switch may be a successful strategy to fight bacterial infections and decrease the emergence of bacterial resistance to antibiotics from a long‐term point of view.     

Diglycine Enables Rapid Intrabacterial Hydrolysis for Activating Anbiotics against Gram‐negative Bacteria

Antimicrobial drug resistance demands novel approaches for improving the efficacy of antibiotics, especially against Gram‐negative bacteria. Herein, we report that conjugating a diglycine (GG) to an antibiotic prodrug drastically accelerates intrabacterial ester‐bond hydrolysis required for activating the antibiotic. Specifically, the attachment of GG to chloramphenicol succinate (CLsu) generates CLsuGG, which exhibits about an order of magnitude higher inhibitory efficacy than CLsu against Escherichia coli. Further studies reveal that CLsuGG undergoes rapid hydrolysis, catalyzed by intrabacterial esterases (e.g., BioH and YjfP), to generate chloramphenicol (CL) in E. coli. Importantly, the conjugate exhibits lower cytotoxicity to bone marrow stromal cells than CL. Structural analogues of CLsuGG indicate that the conjugation of GG to an antibiotic prodrug is an effective strategy for accelerating enzymatic prodrug hydrolysis and enhancing the antibacterial efficacy of antibiotics.     

Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels–Alder Reaction

Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy “handle” for bioreversible derivatization. By taking advantage of an intramolecular Diels–Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti‐inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs.     

A General Strategy for Macrotheranostic Prodrug Activation: Synergy between the Acidic Tumor Microenvironment and Bioorthogonal Chemistry

Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH‐responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor‐specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.     

表面抗菌功能涂层的构建及在生物医用材料中的应用研究

近年来,生物医用材料在使用过程中产生的医源性感染问题层出不穷,对人们健康和生命造成严重威胁.表面抗菌涂层构建是解决该类医源性感染问题最有效的策略之一.目前,按照作用机制和功能不同将表面抗菌涂层分为接触式抗菌涂层、抗黏附抑菌涂层、抗黏附杀菌涂层以及智能抗菌涂层.表面抗菌涂层的构建不仅赋予了生物医用材料抗菌性能,有效解决了上述医源性感染问题,还可以提高材料的生物相容性,赋予其抗黏附、抗氧化、生物识别、传感等功能.本文旨在对目前表面抗菌涂层的种类、构建方法以及其在生物医用材料领域中的应用做一全面论述,为进一步开发高性能表面抗菌涂层并扩展其应用提供新思路.     

Identification and Directed Development of Non‐Organic Catalysts with Apparent Pan‐Enzymatic Mimicry into Nanozymes for Efficient Prodrug Conversion

Nanozymes, nanoparticles that mimic the natural activity of enzymes, are intriguing academically and are important in the context of the Origin of Life. However, current nanozymes offer mimicry of a narrow range of mammalian enzymes, near‐exclusively performing redox reactions. We present an unexpected discovery of non‐proteinaceous enzymes based on metals, metal oxides, 1D/2D‐materials, and non‐metallic nanomaterials. The specific novelty of these findings lies in the identification of nanozymes with apparent mimicry of diverse mammalian enzymes, including unique pan‐glycosidases. Further novelty lies in the identification of the substrate scope for the lead candidates, specifically in the context of bioconversion of glucuronides, that is, human metabolites and privileged prodrugs in the field of enzyme‐prodrug therapies. Lastly, nanozymes are employed for conversion of glucuronide prodrugs into marketed anti‐inflammatory and antibacterial agents, as well as “nanozyme prodrug therapy” to mediate antibacterial measures.     

Simultaneous Application of Photothermal Therapy and an Anti‐inflammatory Prodrug using Pyrene–Aspirin‐Loaded Gold Nanorod Graphitic Nanocapsules

Photothermal therapy (PTT) has been extensively developed as an effective approach against cancer. However, PTT can trigger inflammatory responses, in turn simulating tumor regeneration and hindering subsequent therapy. A therapeutic strategy was developed to deliver enhanced PTT and simultaneously inhibit PTT‐induced inflammatory response. 1‐Pyrene methanol was utilize to synthesize the anti‐inflammatory prodrug pyrene–aspirin (P‐aspirin) with a cleavable ester bond and also facilitate loading the prodrug on gold nanorod (AuNR)‐encapsulated graphitic nanocapsule (AuNR@G), a photothermal agent, through π–π interactions. Such AuNR@G‐P‐aspirin complexes were used for near‐infrared laser‐triggered photothermal ablation of solid tumor and simultaneous inhibition of PTT‐induced inflammation through the release of aspirin in tumor milieu. This strategy showed excellent effects in vitro and in vivo.     

Surface-imprinted polyurethane having affinity sites for ampicillin

Affinity sites for an antibacterial drug, ampicillin, were created on the surface of polyurethane using the technique of non-covalent molecular imprinting. This was achieved by polymerizing aminophenylboronic acid in the presence of the ampicillin as a template. The extent of adsorption of the drug by the imprinted surface is nearly five times higher than the non-imprinted surface. The in vitro release studies have shown that the drug is retained for a prolonged period on the imprinted surface while it is rapidly released from the non-imprinted surface. These modified materials were subjected to interactions with two bacterial strains, E. Coli and S. aureus. These species could not adhere to the imprinted surface, further showing the ability of the surface to retain the drug for a prolonged period of time. The non-imprinted surface retained the bacterial strains, reflecting the lack of the drug on the surface. This novel approach seems to be useful for creating surfaces capable of retaining components of interest through non-covalent interactions to impart specific features, such as improved blood compatibility and antibacterial properties. [diagram in text].     

Smart Titanium Coating Composed of Antibiotic Conjugated Peptides as an Infection‐Responsive Antibacterial Agent

Antibacterial coating is rapidly emerging as a pivotal strategy for mitigating spread of bacterial pathogens. However, many challenges still need to be overcome in order to develop a smart coating that can achieve on‐demand antibacterial effects. In this study, a Staphylococcus aureus (S. aureus) sensitive peptide sequence is designed, and an antibiotic is then conjugated with this tailor‐made peptide. The antibiotic‐peptide conjugate is then linked to the surface of a titanium implant, where the peptide can be recognized and cleaved by an enzyme secreted by S. aureus. This allows for the release of antibiotics in the presence of S. aureus, thus achieving delivery of an antibacterial specifically when an infection occurs.     

Oxazolidinone structure-activity relationships leading to linezolid

The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens which are responsible for significant morbidity and mortality in both the hospital and community settings. A number of solutions to the problem of bacterial resistance are possible. The most common approach is to continue modifying existing classes of antibacterial agents to provide new analogues with improved attributes. Other successful strategies are to combine existing antibacterial agents with other drugs as well as the development of improved diagnostic procedures that may lead to rapid identification of the causative pathogen and permit the use of antibacterial agents with a narrow spectrum of activity. Finally, and most importantly, the discovery of novel classes of antibacterial agents employing new mechanisms of action has considerable promise. Such agents would exhibit a lack of cross-resistance with existing antimicrobial drugs. This review describes the work leading to the discovery of linezolid, the first clinically useful oxazolidinone antibacterial agent.     

Dendrimers as Non-Viral Vectors in Gene-Directed Enzyme Prodrug Therapy

Gene-directed enzyme prodrug therapy (GDEPT) has been intensively studied as a promising new strategy of prodrug delivery, with its main advantages being represented by an enhanced efficacy and a reduced off-target toxicity of the active drug. In recent years, numerous therapeutic systems based on GDEPT strategy have entered clinical trials. In order to deliver the desired gene at a specific site of action, this therapeutic approach uses vectors divided in two major categories, viral vectors and non-viral vectors, with the latter being represented by chemical delivery agents. There is considerable interest in the development of non-viral vectors due to their decreased immunogenicity, higher specificity, ease of synthesis and greater flexibility for subsequent modulations. Dendrimers used as delivery vehicles offer many advantages, such as: nanoscale size, precise molecular weight, increased solubility, high load capacity, high bioavailability and low immunogenicity. The aim of the present work was to provide a comprehensive overview of the recent advances regarding the use of dendrimers as non-viral carriers in the GDEPT therapy.     

Core-Shell Reactor Partitioning Enzyme and Prodrug by ZIF-8 for NADPH-Sensitive In Situ Prodrug Activation

Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core–shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC₅₀ value (26.3±2.6 μg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core–shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.     

Discovery of kibdelomycin, a potent new class of bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus

Bacterial resistance to known therapeutics has led to an urgent need for new chemical classes of antibacterial agents. To address this we have applied?a Staphylococcus aureus fitness test strategy to natural products screening. Here we report the discovery of kibdelomycin, a novel class of antibiotics produced by a new member of the genus Kibdelosporangium. Kibdelomycin exhibits broad-spectrum, gram-positive antibacterial activity and is a potent inhibitor of DNA synthesis. We demonstrate through chemical genetic fitness test profiling and biochemical enzyme assays that kibdelomycin is a structurally new class of bacterial type II topoisomerase inhibitor preferentially inhibiting the ATPase activity of DNA gyrase and topoisomerase IV. Kibdelomycin is thus the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades.     

A Bis(dipyridophenazine)(2‐(2‐pyridyl)pyrimidine‐4‐carboxylic acid)ruthenium(II) Complex with Anticancer Action upon Photodeprotection

Improving the selectivity of anticancer drugs towards cancer cells is one of the main goals of drug optimization; the prodrug strategy has been one of the most promising. A light‐triggered prodrug strategy is presented as an efficient approach for controlling cytotoxicity of the substitutionally inert cytotoxic complex [Ru(dppz)₂(CppH)](PF₆)₂ ( C1 ; CppH=2‐(2‐pyridyl)pyrimidine‐4‐carboxylic acid; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine). Attachment of a photolabile 3‐(4,5‐dimethoxy‐2‐nitrophenyl)‐2‐butyl (DMNPB) ester (“photocaging”) makes the otherwise active complex C1 innocuous to both cancerous (HeLa and U2OS) and non‐cancerous (MRC‐5) cells. The cytotoxic action can be successfully unleashed in living cells upon light illumination (350 nm), reaching similar level of activity as the parent cytotoxic compound C1 . This is the first substitutionally inert cytotoxic metal complex to be used as a light‐triggered prodrug candidate.