Discovery of adjuvants with antibacterial potentiation activity against carbapenemase-producing Enterobacterales based on in silico virtual screening.

Bacterial multi-drug resistance has become a concern worldwide, especially after the emergence of carbapenemases. Adjuvants with antibacterial potentiation activity can resensitise drug-resistant strains to carbapenems. However, only a few adjuvants with antibacterial potentiation activity are currently available in clinical practice. Here, we first docked the library containing more than 30,000 small molecules to carbapenemases including Klebsiella pneumoniae carbapenemase 2 (KPC-2) and New Delhi metallo-ß-lactamase-5 (NDM-5), through in silico virtual screening to obtain lead compounds against carbapenemase-producing Enterobacterales. Meanwhile, the in vitro antibacterial potentiation assays revealed that ibandronate, azacytidine, ribostamycin sulfate and cidofovir exhibited synergistic or additive activity in the presence of meropenem, with good biocompatibility based on red blood cell hemolysis and cell viability tests. Furthermore, the combination of meropenem and azacytidine showed high efficacy in a mouse sepsis model infected with an NDM-5-producing clinical strain, with a 100% survival rate, decreased bacterial burden and alleviated pathological deterioration. These results suggest that the virtual screening is a promising strategy to identify new antibiotic adjuvants targeting carbapenemase-producing Enterobacterales.

Directional droplet bouncing on a moving superhydrophobic surface.

Droplets directionally bouncing off moving superhydrophobic solid surfaces are universal in nature and are crucial in many biological, sustainable, environmental, and engineering applications. However, their underlying physics and regulation strategies remain relatively unknown. This paper demonstrates that the maximum directional acceleration of a post-impact droplet mainly occurs in the spreading stage and that the orientational velocity of the droplet mainly originates in the early impingement process. Furthermore, it clarifies the underlying physics based on momentum transfer process imposed by the boundary layer of impacts and proposes a strategy for regulating the directional droplet velocity using a comprehensive formula. Finally, it shows that directional bouncing reduces the flight momentum of a small flying device by 10%-22%, and the experimental values agree closely with the predicted values. This study reveals the droplet bounce orientation mechanism imposed by moving substrates, provides manipulation methods, and makes positive and meaningful discussions of practical applications.

Synergy of outer membrane disruptor SLAP-S25 with hydrophobic antibiotics against Gram-negative pathogens.

OBJECTIVES: An effective strategy for combating MDR Gram-negative pathogens can greatly reduce the cost and shorten the antibiotic development progress. Here, we investigated the synergistic activity of outer membrane disruptor SLAP-S25 in combination with hydrophobic antibiotics (LogP > 2, including novobiocin, erythromycin, clindamycin and rifampicin) against MDR Gram-negative pathogens. METHODS: Five representative Gram-negative bacteria were selected as model strains to analyse the synergistic combination of SLAP-S25 and hydrophobic antibiotics. Carbapenem-resistant hypervirulent Klebsiella pneumoniae CRHvKP4 was used to investigate the synergistic mechanism. The in vivo synergistically therapeutic activity of SLAP-S25 and hydrophobic antibiotics was measured in the mouse peritonitis/sepsis model infected with K. pneumoniae CRHvKP4. RESULTS: SLAP-S25 disrupted the outer membrane by removing LPS from Gram-negative bacteria, facilitating the entry of hydrophobic antibiotics to kill MDR Gram-negative pathogens. Moreover, the combination of SLAP-S25 and rifampicin exhibited promising therapeutic effects in the mouse infection model infected with K. pneumoniae CRHvKP4. CONCLUSIONS: Our findings provide a potential therapeutic strategy to combine SLAP-S25 with hydrophobic antibiotics for combating MDR Gram-negative pathogens.

Reversible Near-Infrared Fluorescent Probe for Rapid Sensing Sulfur Dioxide and Formaldehyde: Recognition and Photoactivation Mechanism and Applications in Bioimaging and Encryption Ink.

A novel near-infrared (NIR) fluorescent Probe 1 was successfully developed for the reversible detection of sulfur dioxide derivatives and formaldehyde. The purple solution of Probe 1 faded to colorless in 1.8 s with the addition of HSO3-. Meanwhile, its fluorescence signal disappeared instantaneously with a 39 nM detection limit. The probe exhibited excellent selectivity toward HSO3- over other potential interfering agents. Then, its absorption and fluorescence bands were able to effectively recover in response to formaldehyde. Remarkably, this reverse process was able to accelerate 84 times under UV light in 122 s and achieved a recovery rate of 98% by UV light, the photoactivation mechanism was fully determined by HRMS and theoretical calculation. Furthermore, we demonstrated that Probe 1 was successfully applied for the detection of sulfur dioxide derivatives and formaldehyde in living cells and data encryption.

Recent Advances in Biomass-Derived Carbon Materials for Sodium-Ion Energy Storage Devices.

Compared with currently prevailing Li-ion technologies, sodium-ion energy storage devices play a supremely important role in grid-scale storage due to the advantages of rich abundance and low cost of sodium resources. As one of the crucial components of the sodium-ion battery and sodium-ion capacitor, electrode materials based on biomass-derived carbons have attracted enormous attention in the past few years owing to their excellent performance, inherent structural advantages, cost-effectiveness, renewability, etc. Here, a systematic summary of recent progress on various biomass-derived carbons used for sodium-ion energy storage (e.g., sodium-ion storage principle, the classification of bio-microstructure) is presented. Current research on the design principles of the structure and composition of biomass-derived carbons for improving sodium-ion storage will be highlighted. The prospects and challenges related to this will also be discussed. This review attempts to present a comprehensive account of the recent progress and design principle of biomass-derived carbons as sodium-ion storage materials and provide guidance in future rational tailoring of biomass-derived carbons.

Plant Natural Flavonoids Against Multidrug Resistant Pathogens.

The increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens accelerate the desires for new antibiotics. Natural products dominate the preferred chemical scaffolds for the discovery of antibacterial agents. Here, the potential of natural flavonoids from plants against MDR bacteria, is demonstrated. Structure-activity relationship analysis shows the prenylation modulates the activity of flavonoids and obtains two compounds, α-mangostin (AMG) and isobavachalcone (IBC). AMG and IBC not only display rapid bactericidal activity against Gram-positive bacteria, but also restore the susceptibility of colistin against Gram-negative pathogens. Mechanistic studies generally show such compounds bind to the phospholipids of bacterial membrane, and result in the dissipation of proton motive force and metabolic perturbations, through distinctive modes of action. The efficacy of AMG and IBC in four models associated with infection or contamination, is demonstrated. These results suggest that natural products of plants may be a promising and underappreciated reservoir to circumvent the existing antibiotic resistance.

A broad-spectrum antibiotic adjuvant SLAP-S25: one stone many birds.

The rapid emergence of antibiotic resistance has caused serious threat to global health. The worldwide search for novel classes of antibiotics to combat multidrug-resistant (MDR) bacteria is barren since about half a century ago. One of the promising strategies to combat the MDR pathogens is the combinational therapy. For instance, trimethoprim and clavulanic acid are routinely used to enhance the efficacies of sulfonamides and ß-lactam antibiotics in clinic, respectively. Nevertheless, such adjuvants are specific for certain classes of antibiotics. We hypothesized that the combinational treatments with antibiotic adjuvants targeting the bacterial membrane may potentiate other antibiotics against MDR Gram-negative pathogens. In our recent publication (Song et al., doi: 10.1038/s41564-020-0723-z), we demonstrate a short linear antibacterial peptide SLAP-S25, which potentiates multiple antibiotics with different modes of action against Gram-negative bacteria. The mechanism studies show that SLAP-S25 targets both lipopolysaccharide (LPS) in the outer membrane and phosphatidylglycerol (PG) in the inner membrane of Escherichia coli. The impaired bacterial membrane caused by SLAP-S25 promotes the intracellular accumulation of antibiotics in bacteria. Our results indicate that the bacterial membranes are promising targets for the discovery of new antibiotics or antibiotic adjuvants to combat MDR bacteria associated infections.

A broad-spectrum antibiotic adjuvant reverses multidrug-resistant Gram-negative pathogens.

The rapid emergence and dissemination of multidrug-resistant (MDR) bacterial pathogens pose a serious threat to global healthcare. One particular concern is the carbapenem-resistant Enterobacteriaceae (CRE), a group of Gram-negative bacteria that have evolved resistance to all or nearly all available antibiotics. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. We found a short linear antibacterial peptide (SLAP)-S25 carrying four non-natural amino acids of 2,4-diaminobutanoic acid (Dab), which solely showed weak antibacterial activity but boosted the efficacy of antibiotics covering all major classes, including cefepime, colistin, ofloxacin, rifampicin, tetracycline and vancomycin, against MDR Gram-negative pathogens. Mechanistic studies showed that SLAP-S25 triggers membrane damage by binding to both lipopolysaccharide (LPS) in the outer membrane and phosphatidylglycerol (PG) in bacterial cytoplasmic membrane, to potentiate antibiotic efficacy through collaborative strategies. Lastly, SLAP-S25 effectively enhanced the activity of colistin against MDR Escherichia coli-associated infections in three animal models. Our findings provide a potential therapeutic option using existing antibiotics in combination with broad-spectrum antibiotic adjuvants, to address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

Natural Flavones from Morus alba against Methicillin-Resistant Staphylococcus aureus via Targeting the Proton Motive Force and Membrane Permeability.

The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) critically requires alternative therapeutic options. New antibacterial drugs and strategies are urgently needed to combat MRSA-associated infections. Here, we investigated the antibacterial activity of flavones from Morus alba and the potential mode of action against MRSA. Kuwanon G, kuwanon H, mulberrin, and morusin displayed high efficiency in killing diverse MRSA isolates. On the basis of structure-activity analysis, the cyclohexene-phenyl ketones and isopentenyl groups were critical to increase the membrane permeability and to dissipate the proton motive force. Meanwhile, mechanistic studies further showed that kuwanon G displayed rapid bactericidal activity in vitrowith difficulty in developing drug resistance. Kuwanon G targeted phosphatidylglycerol and cardiolipin in the cytoplasmic membrane through the formation of hydrogen bonds and electrostatic interactions. Additionally, kuwanon G promoted wound healing in a mouse model of MRSA skin infection. In summary, these results indicate that flavones are promising lead compounds to treat MRSA-associated infections through disrupting the proton motive force and membrane permeability.

Enhancing Droplet Deposition on Wired and Curved Superhydrophobic Leaves.

Droplet deposition on superhydrophobic surfaces has been a great challenge owing to the shortness of the impact contact time. Despite recent research progress regarding flat superhydrophobic surfaces, improving deposition on ubiquitous wired and curved superhydrophobic leaves remains challenging as their surface structures promote asymmetric impacts, thereby shortening the contact times and increasing the likelihood of droplet splitting. Here, we propose a strategy to solve the deposition problems based on an analysis of the impact dynamics and a rational selection of additives. Combining the prominent extension property of flexible polymers with surface tension reduction of the surfactant, the well-chosen binary additives cooperatively solve retention and coverage problems by limiting the fragment and enhancing local pinning and wetting processes at a very low usage. This work advances the understanding of droplet deposition by rationally selecting additives based on the impact dynamics, which is believed to be useful in a variety of spraying, coating, and printing applications.

Macrolides induce severe cardiotoxicity and developmental toxicity in zebrafish embryos.

Macrolide antibiotics (MALs) are widely used for both human and animal health. Most MALs and their metabolites transfer into aquatic organisms and environment resulting in violent consequences. Previous studies show that MALs cause cardiotoxicity in humans and mammals. However, the potential risk of these chemicals in aquatic organisms remains unclear. Here, we used zebrafish embryos as a model to evaluate the toxicity of MALs. Zebrafish embryos were exposed to four typical MALs including azithromycin (AZM), clarithromycin (CLR), tilmicosin (TMS) and tylosin (TYL) to study their cardiotoxicity. The heart rate of zebrafish embryos showed similar biphasic distribution in the presence of four MALs at 2 days post-fertilization (dpf). The heart rate increased significantly at low levels of MALs while decreased obviously at high levels. Subsequently, TMS was chose to study its acute toxicity and developmental toxicity, which caused pericardial edema and spinal curvature in zebrafish embryos at 4 dpf. Furthermore, we found that TMS triggered oxidative stress, with decreased SOD activities and increased MDA contents. Lastly, apoptosis was observed in zebrafish embryos under TMS treatment, with up-regulation of apoptosis associated genes such as p53, bcl 2, bax, caspase 3 and caspase 9, confirmed by increased protein expression based on Western blot analysis. Taken together, these data indicate that MALs can cause serious toxicity in the development of zebrafish. Great caution should be taken due to the huge consumption of MALs for food animal production and treatments with TMS for infections in aquaculture.

Discovery of Linear Low-Cationic Peptides to Target Methicillin-Resistant Staphylococcus aureus in Vivo.

The development and rapid spread of multidrug resistant (MDR) bacteria cause severe public crises. New antibacterial compounds are urgently needed to treat bacterial infections. By circumventing the disadvantages of cationic peptides here, we engineered a short, linear, low-cationic peptide bacaucin-1a, which exhibited remarkable antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Bacaucin-1a was efficient in the prevention of MRSA associated infections in both in vitro and in vivo models with a unique mode of action. The discovery of low-cationic antibiotic candidates will extend our antibiotic pipeline in the fight against antibiotic resistant bacteria.

A nano silicon adjuvant enhances inactivated transmissible gastroenteritis vaccine through activation the Toll-like receptors and promotes humoral and cellular immune responses.

Inactivated transmissible gastroenteritis virus (TGEV) vaccines are widely used in swine herds in China. These are limited, however, by the need to elicit both humoral and cellular immunity, as well as the efficiency of adjuvants. In this study, a 70-nm nano silicon particle was applied with inactivated TGEV vaccine in mice, and its immune-enhancing effects and mechanism of action investigated. We found that nano silicon applied with inactivated TGEV vaccine induced high antibody titers, increase IL-6, TNF-α and IFN-γ expression, and stimulate CD3+ T cell proliferation with a high CD4+/CD8+ T lymphocyte ratio. Nano silicon could quickly activate innate and adaptive immunity by stimulating Toll-like receptor signaling pathways, indicating that the nano silicon adjuvant enhanced long-term humoral and early cellular immune responses when combined with inactivated TGEV vaccine. Nano silicon could be considered for use as an antigen- carrier and adjuvant for veterinary vaccines.

Janus Gradient Meshes for Continuous Separation and Collection of Flowing Oils under Water.

Gradient meshes with Janus wettabilities are fabricated to stably separate and collect spilled oils from a range of flowing oily wastewater. Here, we demonstrate an overflow with separation methodology, which combines selective oil overflow and membrane separation, to separate low content oils from dynamic flowing oil-water mixtures by a curved gradient mesh that covered on a solid edge. The microscaled air-oil-water-solid four-phase wetting state during the oil-water separation process is visualized and demonstrated. The fundamental understanding of this overflow with separation system and the superior gradient mesh materials would enable us to construct a wide variety of separation devices out of traditional designs and advance related applications, such as wastewater treatment and fuel purification.

Controlling liquid splash on superhydrophobic surfaces by a vesicle surfactant.

Deposition of liquid droplets on solid surfaces is of great importance to many fundamental scientific principles and technological applications, such as spraying, coating, and printing. For example, during the process of pesticide spraying, more than 50% of agrochemicals are lost because of the undesired bouncing and splashing behaviors on hydrophobic or superhydrophobic leaves. We show that this kind of splashing on superhydrophobic surfaces can be greatly inhibited by adding a small amount of a vesicular surfactant, Aerosol OT. Rather than reducing splashing by increasing the viscosity via polymer additives, the vesicular surfactant confines the motion of liquid with the help of wettability transition and thus inhibits the splash. Significantly, the vesicular surfactant exhibits a distinguished ability to alter the surface wettability during the first inertial spreading stage of ~2 ms because of its dense aggregates at the air/water interface. A comprehensive model proposed by this idea could help in understanding the complex interfacial interactions at the solid/liquid/air interface.

The controlled release of tilmicosin from silica nanoparticles.

The aim of this study was to use silica nanoparticles as the carrier for controlled release of tilmicosin. Tilmicosin was selected as a drug model molecule because it has a lengthy elimination half-life and a high concentration in milk after subcutaneous administration. Three samples of tilmicosin-loaded silica nanoparticles were prepared with different drug-loading weight. The drug-loading weight in three samples, as measured by thermal gravimetric analysis, was 29%, 42%, and 64%, respectively. With increased drug-loading weight, the average diameter of the drug-loaded silica nanoparticles was increased from 13.4 to 25.7 nm, and the zeta potential changed from-30.62 to-6.78 mV, indicating that the stability of the drug-loaded particles in the aqueous solution decreases as drug-loading weight increases. In vitro release studies in phosphate-buffered saline showed the sample with 29% drug loading had a slow and sustained drug release, reaching 44% after 72 h. The release rate rose with increased drug-loading weight; therefore, the release of tilmicosin from silica nanoparticles was well-controlled by adjusting the drug loading. Finally, kinetics analysis suggested that drug released from silica nanoparticles was mainly a diffusion-controlled process.