An All-In-One Integrating Strategy for Designing Platinum(II)-Based Supramolecular Polymers for Photocatalytic Hydrogen Evolution.

Organic polymer photocatalysts have achieved significant progress in photocatalytic hydrogen evolution, while developing the integrated organic polymers possessing the functions of photosensitizer, electron transfer mediator, and catalyst simultaneously is urgently needed and presents a great challenge. Considering that chalcogenoviologens are able to act as photosensitizers and electron-transfer mediators, a series of chalcogenoviologen-containing platinum(II)-based supramolecular polymers is designed, which exhibited strong visible light-absorbing ability and suitable bandgap for highly efficient photocatalytic hydrogen evolution without the use of a cocatalyst. The hydrogen evolution rate (HER) increases steadily with the decrease in an optical gap of the polymer. Among these "all-in-one" polymers, Se-containing 2D porous polymer exhibited the best photocatalytic performance with a HER of 3.09 mmol g-1 h-1 under visible light (>420 nm) irradiation. Experimental and theoretical calculations reveal that the distinct intramolecular charge transfer characteristics and heteroatom N in terpyridine unit promote charge separation and transfer within the molecules. This work could provide new insights into the design of metallo-supramolecular polymers with finely tuned components for photocatalytic hydrogen evolution from water.

Lusutrombopag as a Repurposing Drug in Combination with Aminoglycosides against Vancomycin-Resistant Enterococcus.

Due to the widespread abuse of antibiotics, drug resistance in Enterococcus has been increasing. However, the speed of antibiotic discovery cannot keep pace with the acquisition of bacterial resistance. Thus, drug repurposing is a proposed strategy to solve the crises. Lusutrombopag (LP) has been approved as a thrombopoietin receptor agonist by the Food and Drug Administration. This study demonstrated that LP exhibited significant antimicrobial activities against vancomycin-resistant Enterococcus in vitro with rare resistance occurrence. Further, LP combined with tobramycin exhibited synergistic antimicrobial effects in vitro and in vivo against Enterococcus. No in vitro or in vivo detectable toxicity was observed when using LP. Mechanism studies indicated that the disrupted proton motive force may account for LP's antimicrobial activity. In summary, these results demonstrate that LP has the previously undocumented potential to serve as an antibacterial agent against refractory infections caused by Enterococcus.

Photoactivated Circularly Polarized Luminescent Organic Radicals in Doped Amorphous Polymer.

Luminescent organic radicals, especially those with photoactivated circularly polarized luminescence (CPL) features, hold great significance for cutting-edge optoelectronic applications, but their development still remains a challenge. In this study, we propose a novel strategy to achieve photoactivated CPL radicals by bonding two phosphine centers within an axial chiral system, yielding a compound of R/S-5,5-bis(diphenylphosphino)-4,4'-bibenzo[d][1,3]dioxole (R/S-BDP). The photoactivated R/S-BDP molecules in polymer matrix display a robust quantum yield of 19.8 % and a dissymmetry factor (glum) of 1.2×10-4, marking this work as the first example of photoactivated CPL radicals. Furthermore, the glum is improved to 1.0×10-2 by using a liquid crystal as host. Experimental and theoretical analyses reveal that R/S-BDP molecules, endowed with double phosphine cores in axial chirality, offer a direct way for intramolecular electron transfer upon photoirradiation. This leads to the generation of radical ionic pairs, which subsequently trigger the donor-acceptor arrangement through intermolecular electron transfer, thereby resulting in stable radical emission. The extended photoactivated BDP-F exhibits a remarkably high quantum efficiency of 57.8%. Ultimately, the distinctive photo-responsive CPL radical luminescence has been successfully used for information displays and anti-counterfeiting.

Insights into the antimicrobial effects of tafenoquine against Enterococcus and its biofilms.

AIM: The purpose of this study is to assess the in vitro antimicrobial and anti-biofilm effects of the anti-protozoal agent tafenoquine (TAF) on Enterococcus and elucidate its underlying mode of action. METHODS AND RESULTS: The present work investigated the susceptibility of TAF on 3 type strains and 11 clinical isolates of enterococci. The results indicated that TAF exhibited powerful antimicrobial activity against both of Enterococcus faecalis and Enterococcus faecium with minimum inhibitory and bactericidal concentrations ranging from 8 to 16 µg ml-1. Meanwhile, biofilm inhibition and eradication assays showed that TAF exhibited potent anti-biofilm activity against E. faecalis ATCC 29212 and E. faecium ATCC 19434. Ultra-microscopic observations revealed significant changes in bacterial morphology and structure caused by TAF, particularly for the disruption of plasma membrane. Mechanistic investigations also revealed that TAF altered both membrane permeability and potential while also impacting adenosine triphosphate production as well as reactive oxygen species generation. In addition, no detectable cytotoxicity of TAF on human cells was observed at concentrations near the minimal inhibitory concentration. CONCLUSIONS: In summary, this study confirmed that TAF could effectively inhibit Enterococcus as well as its biofilm formation.

Repurposing of the antimalarial agent tafenoquine to combat MRSA.

IMPORTANCE: This study represents the first investigation into the antimicrobial effect of TAF against S. aureus and its potential mechanisms. Our data highlighted the effects of TAF against MRSA planktonic cells, biofilms, and persister cells, which is conducive to broadening the application of TAF. Through mechanistic studies, we revealed that TAF targets bacterial cell membranes. In addition, the in vivo experiments in mice demonstrated the safety and antimicrobial efficacy of TAF, suggesting that TAF could be a potential antibacterial drug candidate for the treatment of infections caused by multiple drug-resistant S. aureus.

Simeprevir restores the anti-Staphylococcus activity of polymyxins.

Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a severe threat to global public health due to its high mortality. Currently, polymyxins are mainly used for the treatment of Gram-negative bacterial-related infection, while exhibiting limited antibacterial activities against Staphylococcus aureus (S. aureus). However, the combination of antibiotics with antibiotic adjuvants is a feasible strategy for the hard-treated infection and toxicity reducing. We will investigate the antibacterial activity of simeprevir (SIM), which treated for genotype 1 and 4 chronic hepatitis C, combined with polymyxins against MRSA through high-throughput screening technology. In our study, the synergistic antibacterial effect of SIM and polymyxins against S. aureus in vitro was found by checkerboard assay and time-growth curve. The cytotoxicity of SIM combined with polymyxin B sulfate [PB(S)] or polymyxin E (PE) in vitro was evaluated using CCK-8, human RBC hemolysis and scratch assays. In addition, we investigated the eradication of biofilm formation of S. aureus by biofilm inhibition assay and the killing of persister cells. Moreover, we evaluated the therapeutic effect and in vivo toxicity of the combination against MRSA in murine subcutaneous abscess model. Furthermore, it was preliminarily found that SIM significantly enhanced the destruction of MRSA membrane by SYTOX Green and DISC3(5) probes. In summary, these results reveal that the therapy of SIM combined with polymyxins (especially PE) is promising for the treatment of MRSA infection.

HIV-1-related factors interact with p53 to influence cellular processes.

Human immunodeficiency virus type 1 (HIV-1) is the primary epidemic strain in China. Its genome contains two regulatory genes (tat and rev), three structural genes (gag, pol, and env), and four accessory genes (nef, vpr, vpu, and vif). Long terminal repeats (LTRs) in thegenome regulate integration, duplication, and expression of viral gene. The permissibility of HIV-1 infection hinges on the host cell cycle status. HIV-1 replicates by exploiting various cellular processes via upregulation or downregulation of specific cellular proteins that also control viral pathogenesis. For example, HIV-1 regulates the life cycle of p53, which in turn contributes significantly to HIV-1 pathogenesis. In this article, we review the interaction between HIV-1-associated factors and p53, providing information on their regulatory and molecular mechanisms, hinting possible directions for further research.

Inhibitory effects of simeprevir on Staphylococcusepidermidis and itsbiofilm in vitro. / è¥¿å’ªåŒ¹éŸ¦å¯¹è¡¨çš®è‘¡è„çƒèŒåŠå ¶ç”Ÿç‰©è†œçš„ä½“å¤–æŠ‘åˆ¶ä½œç”¨.

OBJECTIVES: Staphylococcus epidermidis (S. epidermidis) is a Gram-positive opportunistic pathogen that often causes hospital infections. With the abuse of antibiotics, the resistance of S. epidermidis gradually increases, and drug repurposing has become a research hotspot in the treating of refractory drug-resistant bacterial infections. This study aims to study the antimicrobial and antibiofilm effects of simeprevir, an antiviral hepatitis drug, on S. epidermidis in vitro. METHODS: The micro-dilution assay was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of simeprevir against S. epidermidis. Crystal violet staining assay was used to detect the biofilm inhibitory effect of simeprevir. The antimicrobial activity of simeprevir against S. epidermidis and its biofilm were explored by SYTO9/PI fluorescent staining. The combined effect between simeprevir and gentamycin was assessed by checkerboard assay and was confirmed by time-inhibition assay. RESULTS: Simeprevir showed significant antimicrobial effects against S. epidermidis type strains and clinical isolates with the MIC and MBC at 2-16 µg/mL and 4-32 µg/mL, respectively. The antimicrobial effects of simeprevir were confirmed by SYTO9/PI staining. Simeprevir at MIC could significantly inhibit and break the biofilm on cover slides. Similarly, simeprevir also significantly inhibit the biofilm formation on the surface of urine catheters either in TSB [from (0.700±0.020) to (0.050±0.004)] (t=54.03, P<0.001), or horse serum [from (1.00±0.02) to (0.13±0.01)] (t=82.78, P<0.001). Synergistic antimicrobial effect was found between simeprevir and gentamycin against S. epidermidis with the fractional inhibitory concentration index of 0.5. CONCLUSIONS: Simeprevir shows antimicrobial effect and anti-biofilm activities against S. epidermidis.

Repurposing 9-Aminoacridine as an Adjuvant Enhances the Antimicrobial Effects of Rifampin against Multidrug-Resistant Klebsiella pneumoniae.

The increasing occurrence of extensively drug-resistant and pan-drug-resistant K. pneumoniae has posed a serious threat to global public health. Therefore, new antimicrobial strategies are urgently needed to combat these resistant K. pneumoniae-related infections. Drug repurposing and combination are two effective strategies to solve this problem. By a high-throughput screening assay of FDA-approved drugs, we found that the potential small molecule 9-aminoacridine (9-AA) could be used as an antimicrobial alone or synergistically with rifampin (RIF) against extensively/pan-drug-resistant K. pneumoniae. In addition, 9-AA could overcome the shortcomings of RIF by reducing the occurrence of resistance. Mechanistic studies revealed that 9-AA interacted with bacterial DNA and disrupted the proton motive force in K. pneumoniae. Through liposomeization and combination with RIF, the cytotoxicity of 9-AA was significantly reduced without affecting its antimicrobial activity. In addition, we demonstrated the in vivo antimicrobial activity of 9-AA combined with RIF without detectable toxicity. In summary, 9-AA has the potential to be an antimicrobial agent or a RIF adjuvant for the treatment of multidrug-resistant K. pneumoniae infections. IMPORTANCE Klebsiella pneumoniae is a leading cause of clinically acquired infections. The increasing occurrence of drug-resistant K. pneumoniae has posed a serious threat to global public health. We found that the potential small molecule 9-AA could be used as an antimicrobial alone or synergistically with RIF against drug-resistant K. pneumoniae in vitro and with low resistance occurrence. The combination of 9-AA or 9-AA liposomes with RIF possesses effective antimicrobial activity in vivo without detected toxicity. 9-AA exerted its antimicrobial activity by interacting with specific bacterial DNA and disrupting the proton motive force in K. pneumoniae. In summary, we found that 9-AA has the potential to be developed as a new antibacterial agent and adjuvant for RIF. Therefore, our study can reduce the risk of antimicrobial resistance and provide an option for the exploitation of new clinical drugs and a theoretical basis for the research on a new antimicrobial agent.

Antibacterial and antibiofilm efficacy of repurposing drug hexestrol against methicillin-resistant Staphylococcus aureus.

There has been an explosion in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) because of the indiscriminate use of antibiotics. In this study, we repurposed hexestrol (HXS) as an antibacterial agent to fight planktonic and biofilm-related MRSA infections. HXS is a nonsteroidal synthetic estrogen that targets estrogen receptors (ERα and ERß) and has been used as a hormonal antineoplastic agent. In our work, the minimum inhibitory concentrations (MICs) were determined using the antimicrobial susceptibility of MSSA and MRSA strains. Anti-biofilm activity was evaluated using biofilm inhibition and eradication assays. Biofilm-related genes were analyzed with or without HXS treatment using RTqPCR analysis of S. aureus. HXS was tested using the checkerboard dilution assay to identify antibiotics that may have synergistic effects. Measurement of ATP and detection of ATPase allowed the determination of bacterial energy metabolism. As shown in the results, HXS showed effective antimicrobial activity against S. aureus, including both type strains and clinical isolations, with MICs of 16 µg/mL. Sub-HXS strongly inhibited the adhesion of S. aureus. The content of extracellular polymeric substances (EPS) and the relative transcription levels of eno, sacC, clfA, pls and fnbpB were reduced after HXS treatment. HXS showed antibacterial effects against S. aureus and synergistic activity with aminoglycosides by directly interfering with cellular energy metabolism. HXS inhibits adhesion and biofilm formation and eradicates biofilms formed by MRSA by reducing the expression of related genes. Furthermore, HXS increases the susceptibility of aminoglycosides against MRSA. In conclusion, HXS is a repurposed drug that may be a promising therapeutic option for MRSA infection.

Triple combination of SPR741, clarithromycin, and erythromycin against Acinetobacter baumannii and its tolerant phenotype.

AIMS: Extensively drug-resistant (XDR) Acinetobacter baumannii poses a severe threat to public health due to its ability to form biofilms and persister cells, which contributes to critical drug resistance and refractory device-associated infections. A novel strategy to alleviate such an emergency is to identify promising compounds that restore the antimicrobial susceptibility of existing antibiotics against refractory infections. METHODS AND RESULTS: Here, we found a significant synergy among three combinations of SPR741, clarithromycin and erythromycin with a potent antimicrobial activity against XDR A. baumannii (SPR741/CLA/E at 8/10/10 µg ml-1 for XDR AB1069 and at 10/16/10 µg ml-1 for XDR AB1208, respectively). Moreover, the triple combination therapy exhibits a significant antipersister and antibiofilm effect against XDR strains. Mechanistic studies demonstrate that SPR741 may promote intracellular accumulation of macrolides by permeabilizing the outer membrane as well as disrupting membrane potential and further enhance the quorum sensing inhibition activity of the macrolides against XDR A. baumannii and its biofilms. In addition, the triple combination of SPR741 with clarithromycin and erythromycin was not easy to induce resistance in A. baumannii and had effective antimicrobial activity with low toxicity in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY: Collectively, these results reveal the potential of SPR741 in combination with clarithromycin and erythromycin as a clinical therapy for refractory infections caused by XDR A. baumannii.

Drug synergy discovery of tavaborole and aminoglycosides against Escherichia coli using high throughput screening.

High incidences of urinary tract infection (UTI) of aminoglycosides-resistant E.coli causes a severe burden for public health. A new therapeutic strategy to ease this crisis is to repurpose non-antibacterial compounds to increase aminoglycosides sensibility against multidrug resistant E.coli pathogens. Based on high throughput screening technology, we profile the antimicrobial activity of tavaborole, a first antifungal benzoxaborole drug for onychomycosis treatment, and investigate the synergistic interaction between tavaborole and aminoglycosides, especially tobramycin and amikacin. Most importantly, by resistance accumulation assay, we found that, tavaborole not only slowed resistance occurrence of aminoglycosides, but also reduced invasiveness of E.coli in combination with tobramycin. Mechanistic studies preliminary explored that tavaborole and aminoglycosides lead to mistranslation, but would be still necessary to investigate more details for further research. In addition, tavaborole exhibited low systematic toxicity in vitro and in vivo, and enhanced aminoglycoside bactericidal activity in mice peritonitis model. Collectively, these results suggest the potential of tavaborole as a novel aminoglycosides adjuvant to tackle the clinically relevant drug resistant E. coli and encourages us to discover more benzoxaborole analogues for circumvention of recalcitrant infections.

Insights into the antimicrobial effects of ceritinib against Staphylococcus aureus in vitro and in vivo by cell membrane disruption.

According to a 2019 report from the Centers of Disease Control and Prevention (CDC), methicillin-resistant Staphylococcus aureus (MRSA) was listed as one of the "serious threats" that had become a global public challenge in hospitals and community. Biofilm-associated infections and refractory persisters of S. aureus also impede the effectiveness of conventional antibiotics that have greatly increased difficulty in clinical therapy. There is an urgent need to develop new antimicrobials with antibiofilm and anti-persister capacities, and drug repurposing is the most effective and most economical solution to the problem. The present study profiles the antimicrobial activity of ceritinib, a tyrosine kinase inhibitor, against S. aureus in vitro and in vivo. We investigated the antimicrobial efficacy of ceritinib against planktonic and persistent S. aureus by a time-killing kinetics assay. Then, antibiofilm effect of ceritinib was assessed by crystal violet staining and laser confocal microscope observation. Ceritinib showed biofilm inhibition and mature biofilm eradication, and possesses robust bactericidal activity against S. aureus persisters. We also evaluated antimicrobial efficacy in vivo using a subcutaneous abscess infection model. Ceritinib ameliorated infection in a subcutaneous abscess mouse model and only showed negligible systemic toxicity in vivo. Mechanism exploration was conducted by transmission electron microscopy, fluorescently labeled giant unilamellar vesicle assays, and a series of fluorescent dyes. In conclusion, we find ceritinib represents potential bactericidal activity against MRSA by disrupting cell membrane integrity and inducing reactive oxygen species production, suggesting ceritinib has the potential to treat MRSA-related infections.

Pixantrone Sensitizes Gram-Negative Pathogens to Rifampin.

The emergence of bacterial drug resistance poses a severe threat to global public health. In particular, antimicrobial-resistant pathogens lead to a high rate of treatment failure and significantly increase mortality. Repurposing FDA-approved compounds to sensitize superbugs to conventional antibiotics provides a promising strategy to alleviate such crises. Pixantrone (PIX) has been approved for treating aggressive B-cell non-Hodgkin's lymphoma. By high-throughput drug screening, we profiled the synergistic activity between PIX and rifampin (RFP) against Gram-negative extensively drug-resistant isolates by checkerboard assay. Mechanistic studies demonstrated that PIX impacted the flagellum assembly, induced irreversible intracellular reactive oxygen species accumulation and disrupted proton motive force. In addition, the combination of PIX with RFP possesses effective antimicrobial activity against multidrug-resistant strains in vivo without detected toxicity. Collectively, these results reveal the potential of PIX in combination with RFP as a therapy option for refractory infections caused by Gram-negative pathogens. IMPORTANCE Bacterial resistance has become increasingly serious because of the widespread use and abuse of antibiotics. In particular, the emergence of multidrug-resistant bacteria has posed a serious threat to human public health. Drug repurposing, the process of finding new uses for existing drugs, provide a promising pathway to solve antimicrobial resistance. Compared to the development of novel antibiotics, this strategy leverages well-characterized pharmacology and toxicology of known drugs and is more cost-effective.

SPR741, Double- or Triple-Combined With Erythromycin and Clarithromycin, Combats Drug-Resistant Klebsiella pneumoniae, Its Biofilms, and Persister Cells.

Klebsiella pneumoniae has emerged as a major clinical and public health threat owing to the increasing prevalence of healthcare-associated infections caused by multidrug-resistant or extensively drug-resistant strains. However, increasing antibiotic resistance and the absence of clinically effective antimicrobial agents make combination therapy an urgent need. This study investigated the anti-microbial activity of SPR741, a polymyxin B derivative, in combination with macrolide antibiotics (erythromycin and clarithromycin), against extensively drug-resistant and pandrug-resistant K. pneumoniae. Monotherapy, double, and triple combination therapies were performed to identify the most effective treatment combination using in vitro checkerboard, time-killing kinetics. Furthermore, we evaluated the biofilm eradication and persister cell-killing activity of these combinations using laser confocal microscopy and colony forming unit counting. In addition, a neutropenic mouse thigh infection model was used to assess the therapeutic efficacy and toxicity of the triple antibiotic combination against pandrug-resistant K. pneumoniae in vivo. Our results suggested that SPR741 combined with macrolides exhibited strong synergistic antibacterial activity against extensively drug-resistant and pandrug-resistant K. pneumoniae. These antibiotic combinations could also effectively eradicate highly resistant bacterial biofilms and persister cells in vitro and demonstrate considerable efficacy and low toxicity in vivo. In summary, our findings indicated that SPR741, in combination with macrolide antibiotics (double or triple combination), has the potential to serve as a novel treatment option against drug-resistant K. pneumoniae -related infections.

Anti-hepatitis C virus drug simeprevir: a promising antimicrobial agent against MRSA.

Staphylococcus aureus is a major human pathogen, and the appearance of methicillin-resistant S. aureus (MRSA) renders S. aureus infections more challenging to treat. Therefore, new antimicrobial drugs are urgently needed to combat MRSA infections. Drug repurposing is an effective and feasible strategy. Here, we reported that the clinically approved anti-hepatitis C virus drug simeprevir had strong antibacterial activity against MRSA, with a minimum inhibitory concentration of 2-8 µg/mL. Simeprevir did not easily induce in vitro resistance. In addition, simeprevir significantly prevented S. aureus biofilm formation. Furthermore, simeprevir displayed limited toxicity in in vitro and in vivo assays. Moreover, simeprevir showed synergistic antimicrobial effects against both type and clinical strains of S. aureus. Simeprevir combined with gentamicin effectively reduced the bacterial burden in an MRSA-infected subcutaneous abscess mouse model. Results from a series of experiments, including membrane permeability assay, membrane potential assay, intracellular ATP level assay, and electron microscope observation, demonstrated that the action of simeprevir may be by disrupting bacterial cell membranes. Collectively, these results demonstrated the potential of simeprevir as an antimicrobial agent for the treatment of MRSA infections. KEY POINTS: • Simeprevir showed strong antibacterial activity against MRSA. • The antibacterial mechanism of simeprevir was mediated by membrane disruption and intracellular ATP depletion. • In vitro and in vivo synergistic antimicrobial efficacy between simeprevir and gentamicin was found.

A novel bactericidal small molecule, STK-35, and its derivative, STK-66, as antibacterial agents against Gram-negative pathogenic bacteria in vitro and in vivo.

Due to the increasing rate of antibiotic resistance and the emergence of persister cells of Gram-negative pathogenic bacteria, the development of new antibacterial agents is urgently needed to deal with this problem. Our results indicated that both newly identified small molecule STK-35 and its derivative STK-66 exhibited effective antibacterial properties against a variety of Gram-negative pathogens including Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The minimal inhibitory concentrations and minimal bactericidal concentrations ranges were 0·0625-8 µg ml-1 and 0·125-16 µg ml-1 , respectively, while no haemolytic activity and mammalian cell cytotoxicity were observed. The time-killing assays showed STK-35/66 had strong bactericidal activity against Gram-negative pathogens. STK-35/66 also showed different degrees of synergistic antibacterial activity with conventional antibiotics and exhibited persister cells killing activity. Moreover, STK-35/66 effectively eradicated the pre-formed biofilms of P. aeruginosa and A. baumannii. In addition, STK-35/66 significantly increased the survival rate of E. coli infected mice and induced a decrease in bacterial load of the peritonitis model. In nutshell, these results suggested that STK-35/66 possessed antimicrobial activity against Gram-negative pathogenic bacteria in vitro and in vivo, which could be considered as potential substitutes for the treatment of Gram-negative pathogenic infections after further structure optimization.

Identification of a small molecule 0390 as a potent antimicrobial agent to combat antibiotic-resistant Escherichia coli.

Introduction: Antibiotic resistance has posed a serious challenge to global public health. With the increasing resistance emergence of E. coli and mortality caused by drug-resistant E. coli infections, it is urgent to develop novel antibiotics. Methods: By high-throughput screening assay, we found a bioactive molecule, 0390 (6056-0390), which demonstrated antimicrobial effects against E. coli. The antimicrobial effects of 0390 alone or in combination with conventional antibiotics were assessed by scanning electron microscopy, transmission electron microscopy, drug combination assay, and growth inhibition assay. In addition, we investigated the antimicrobial efficacy in subcutaneous infection model in vivo. Results: 0390 showed significant synergistic antimicrobial effects in combination with SPR741, a polymyxin B derivative, against E. coli standard strain and extensively drug-resistant (XDR) clinical isolates, and the combination exhibited good safety property in vitro. In addition, we demonstrated that the combinational treatment of 0390 and SPR741 exhibited a considerable antibacterial activity in vivo, and no tissue damage or other toxicity was observed after the therapeutic dose treatment. Discussion: To confront the issue of the infectious diseases related to E. coli and its multidrug resistant strains, potential approaches, such as new antibacterial agents with different structures from conventional antibiotics and drug combinations, are urgently needed. In this study, we have determined the in vitro and in vivo antimicrobial potential of 0390 alone or in combination with SPR741, which might be used as a treatment option for E. coli related infections.

Recent Progress in External-Stimulus-Responsive 2D Covalent Organic Frameworks.

Recently, smart 2D covalent organic frameworks (COFs), combining the advantages of both inherent structure features and functional building blocks, have been demonstrated to show reversible changes in conformation, color, and luminescence in response to external stimuli. This review provides a summary on the recent progress of 2D COFs that are responsive to external stimuli such as metal ions, gas molecules, pH values, temperature, electricity, light, etc. Moreover, the responsive mechanisms and design strategies, along with the applications of these stimulus-responsive 2D COFs in chemical sensors and photoelectronic devices are also discussed. It is believed that this review would provide some guidelines for designing novel single-/multistimulus-responsive 2D COFs with controllable responsive behaviors for advanced photoelectronic applications.

Repurposing Sitafloxacin, Prulifloxacin, Tosufloxacin, and Sisomicin as Antimicrobials Against Biofilm and Persister Cells of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a ubiquitous bacterium found in hospitals and the surrounding environment. The ability of P. aeruginosa to form biofilms confers high-level resistance to antibiotics, and the persister cells formed in the presence of high antibacterial drug concentrations make P. aeruginosa-related infections more refractory. Further, there rarely is an effective antimicrobial alternative when biofilm- and persister cell-targeting treatment fails. Using a high-throughput screening assay, we previously identified fluoroquinolones sitafloxacin, prulifloxacin, and tosufloxacin as well as aminoglycoside sisomicin among FDA-approved drugs with significant bactericidal activity against P. aeruginosa. In addition, in our current study, these antibiotics exhibited an effective time- and dose-dependent eradication effects against the preformed biofilms of P. aeruginosa at the concentrations of 2-4 µM. These agents also exhibited bactericidal efficacy against CCCP-induced P. aeruginosa persister cells with the viable cell count decreased from 9.14 log10 CFU/mL to 6.15 (sitafloxacin), 7.59 (prulifloxacin), 4.27 (tosufloxacin), and 6.17 (sisomicin) log10 CFU/mL, respectively, following 4 h of treatment. Furthermore, sisomicin was also effective against conventional antibiotics induced persister cells in a time-dependent manner within 24 h. In addition, we confirmed the in vivo anti-biofilm efficacy of the identified antibiotics in a subcutaneous implantation biofilm-related infection model. Tosufloxacin exhibited the greatest in vivo bactericidal activity against P. aeruginosa biofilms with a reduction of 4.54 ΔLog10 CFU/mL compared to the vehicle group, followed by prulifloxacin, sitafloxacin, and sisomicin. Taken together, our results indicate that sitafloxacin, prulifloxacin, tosufloxacin, and sisomicin have great potential as alternatives for the treatment of refractory infections caused by P. aeruginosa biofilms and persister cells.