Photocatalytic degradation of parabens: A comprehensive meta-analysis investigating the environmental remediation potential of emerging pollutant.

The increasing prevalence of paraben compounds in the environment has given rise to concerns regarding their detrimental impacts on both ecosystems and human health. Over the past few decades, photocatalytic reactions have drawn significant attention as a method to accelerate the otherwise slow degradation of these pollutants. The current study aims to evaluate the current efficacy of the photocatalytic method for degrading parabens in aqueous solutions. An extensive literature review and bibliometric analysis were conducted to identify key research trends and influential areas in the field of photocatalytic paraben degradation. Studies were screened based on the predetermined inclusion and exclusion criteria, which led to 13 studies that were identified as being appropriate for the meta-analysis using the random effects model. Furthermore, experimental parameters such as pH, paraben initial concentration, catalyst dosage, light intensity, and contact time have been reported to have key impacts on the performance of the photocatalytic degradation process. A comprehensive quantitative assessment of these parameters was carried out in this work. Overall, photocatalytic techniques could eliminate parabens with an average degradation efficiency of >80 %. The findings of the Egger's test and the Begg's test were statistically not significant suggesting potential publication bias was not observed. This review provides a holistic understanding of the photocatalytic degradation of parabens and is anticipated to encourage more widespread adoption of photocatalytic procedures as a suitable method for the elimination of parabens from aqueous solutions, opening new avenues for future research in this direction.

Dysregulation of tyrosinase activity: a potential link between skin disorders and neurodegeneration.

OBJECTIVES: The co-occurrence of melanoma and Parkinson's disease (PD) is higher than expected. We review the relationship between melanoma and PD, then proffer a hypothesis of how dysregulated human tyrosinase could be involved in both diseases via the loss of dopamine and neuromelanin-positive neurons in PD and the genesis alterations in melanin content during melanoma. KEY FINDINGS: There are a surprising number of links between skin disorders and neurodegenerative diseases. Some risk factors related to the co-occurrence of PD and melanoma have been extensively investigated over the past 15 years. It has been proposed that human tyrosinase, an enzyme participating in the biosynthesis of neuromelanin in the brain and of melanin in the skin, plays a role. Abnormally dysregulated human tyrosinase impacts the genesis and progression of melanoma and PD. SUMMARY: The dual role of human tyrosinase places it as the potential critical link between these seemingly distinct conditions. Detecting and monitoring human tyrosinase activity in the progression of melanoma and PD opens new opportunities for early diagnosis and treatment of both diseases.

The Antimicrobial Properties of PdII - and RuII -pyta Complexes.

Infections associated with antimicrobial resistance (AMR) are poised to become the leading cause of death in the next few decades, a scenario that can be ascribed to two phenomena: antibiotic over-prescription and a lack of antibiotic drug development. The crowd-sourced initiative Community for Open Antimicrobial Drug Discovery (CO-ADD) has been testing research compounds contributed by researchers around the world to find new antimicrobials to combat AMR, and during this campaign has found that metallodrugs might be a promising, yet untapped source. To this end, we submitted 18 PdII - and RuII -pyridyl-1,2,3-triazolyl complexes that were developed as catalysts to assess their antimicrobial properties. It was found that the Pd complexes, especially Pd1, possessed potent antifungal activity with MICs between 0.06 and 0.125 µg mL-1 against Candida glabrata. The in-vitro studies were extended to in-vivo studies in Galleria mellonella larvae, where it was established that the compounds were nontoxic. Here, we effectively demonstrate the potential of PdII -pyta complexes as antifungal agents.

Impact of the new membrane-targeting lipoglycopeptide antibiotic MCC5145 on the treatment of bacteremic pneumococcal pneumonia in mice.

Bacteremic Streptococcus pneumoniae pneumonia is one of the most severe forms of invasive pneumococcal disease (IPD) and with particularly high case-fatality rates among the elderly and individuals with comorbidities, exacerbated by rising antibiotic resistance and time to initiation of therapy. Here, we examined the efficacy of the preclinical "vancapticin" glycopeptide MCC5145 against fulminant infection by S. pneumoniae serotype 2 strain D39 in a bioluminescent, neutropenic mouse model of bacteremic pneumonia. MCC5145 is a semisynthetic vancomycin derivative chemically modified at the C-terminus with a membrane-targeting motif designed to preferentially bind the anionic bacterial surface. We show that similar to vancomycin, subcutaneous administration of MCC5145 to mice 1 day after intranasal infection with a bioluminescent derivative of S. pneumoniae D39 elicited time and concentration-dependent reduction in total flux in the lungs and blood. Together, our finding supports the further development of MCC5145 as a potential new treatment option for pneumonia and/or bacteremic pneumonia in clinical settings, particularly for immunocompromised individuals. IMPORTANCE S. pneumoniae (the pneumococcus) causes severe community acquired lung and blood infection, especially among the elderly and people with underlying medical conditions and/or weakened immune systems. The rising incidence of antibiotic resistance and delays between diagnosis of infection and commencement of effective therapy make treatment difficult and result in high mortality rates. In this work, we show that a new derivative (MCC5145) of an existing antibiotic (vancomycin) rapidly eradicated lethal pneumococcal challenge from the lungs and blood of mice with a suppressed immune system. Our findings support that MCC5145 is a promising option for the treatment of lung and blood infections caused by the pneumococcus at point-of-care settings, particularly for the elderly and individuals with a weakened immune system.

Natural products as anthelmintics: safeguarding animal health.

Covering literature to December 2022This review provides a comprehensive account of all natural products (500 compounds, including 17 semi-synthetic derivatives) described in the primary literature up to December 2022, reported to be capable of inhibiting the egg hatching, motility, larval development and/or the survival of helminths (i.e., nematodes, flukes and tapeworms). These parasitic worms infect and compromise the health and welfare, productivity and lives of commercial livestock (i.e., sheep, cattle, horses, pigs, poultry and fish), companion animals (i.e., dogs and cats) and other high value, endangered and/or exotic animals. Attention is given to chemical structures, as well as source organisms and anthelmintic properties, including the nature of bioassay target species, in vivo animal hosts, and measures of potency.

Antibiotics in the clinical pipeline as of December 2022.

The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and ß-lactam/ß-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed.

Quantifying the Economic and Clinical Value of Reducing Antimicrobial Resistance in Gram-negative Pathogens Causing Hospital-Acquired Infections in Australia.

INTRODUCTION: Antimicrobial resistance (AMR) is a global public health challenge requiring a global response to which Australia has issued a National Antimicrobial Resistance Strategy. The necessity for continued-development of new effective antimicrobials is required to tackle this immediate health threat is clear, but current market conditions may undervalue antimicrobials. We aimed to estimate the health-economic benefits of reducing AMR levels for drug-resistant gram-negative pathogens in Australia, to inform health policy decision-making. METHODS: A published and validated-dynamic health economic model was adapted to the Australian setting. Over a 10-year time horizon, the model estimates the clinical and economic outcomes associated with reducing current AMR levels, by up to 95%, of three gram-negative pathogens in three hospital-acquired infections, from the perspective of healthcare payers. A willingness-to-pay threshold of AUD$15,000-$45,000 per quality-adjusted life-year (QALY) gained and a 5% discount rate (for costs and benefits) were applied. RESULTS: Over ten years, reducing AMR for gram-negative pathogens in Australia is associated with up to 10,251 life-years and 8924 QALYs gained, 9041 bed-days saved and 6644 defined-daily doses of antibiotics avoided. The resulting savings are estimated to be $10.5 million in hospitalisation costs, and the monetary benefit at up to $412.1 million. DISCUSSION: Our results demonstrate the clinical and economic value of reducing AMR impact in Australia. Of note, since our analysis only considered a limited number of pathogens in the hospital setting only and for a limited number of infection types, the benefits of counteracting AMR are likely to extend well beyond the ones demonstrated here. CONCLUSION: These estimates demonstrate the consequences of failure to combat AMR in the Australian context. The benefits in mortality and health system costs justify consideration of innovative reimbursement schemes to encourage the development and commercialisation of new effective antimicrobials.

Siderophore conjugates to combat antibiotic-resistant bacteria.

Antimicrobial resistance (AMR) is a global threat to society due to the increasing emergence of multi-drug resistant bacteria that are not susceptible to our last line of defence antibiotics. Exacerbating this issue is a severe gap in antibiotic development, with no new clinically relevant classes of antibiotics developed in the last two decades. The combination of the rapidly increasing emergence of resistance and scarcity of new antibiotics in the clinical pipeline means there is an urgent need for new efficacious treatment strategies. One promising solution, known as the 'Trojan horse' approach, hijacks the iron transport system of bacteria to deliver antibiotics directly into cells - effectively tricking bacteria into killing themselves. This transport system uses natively produced siderophores, which are small molecules with a high affinity for iron. By linking antibiotics to siderophores, to make siderophore antibiotic conjugates, the activity of existing antibiotics can potentially be reinvigorated. The success of this strategy was recently exemplified with the clinical release of cefiderocol, a cephalosporin-siderophore conjugate with potent antibacterial activity against carbapenem-resistant and multi-drug resistant Gram-negative bacilli. This review discusses the recent advancements in siderophore antibiotic conjugates and the challenges associated with the design of these compounds that need to be overcome to deliver more efficacious therapeutics. Potential strategies have also been suggested for new generations of siderophore-antibiotics with enhanced activity.

Synthesis of vancomycin fluorescent probes that retain antimicrobial activity, identify Gram-positive bacteria, and detect Gram-negative outer membrane damage.

Antimicrobial resistance is an urgent threat to human health, and new antibacterial drugs are desperately needed, as are research tools to aid in their discovery and development. Vancomycin is a glycopeptide antibiotic that is widely used for the treatment of Gram-positive infections, such as life-threatening systemic diseases caused by methicillin-resistant Staphylococcus aureus (MRSA). Here we demonstrate that modification of vancomycin by introduction of an azide substituent provides a versatile intermediate that can undergo copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction with various alkynes to readily prepare vancomycin fluorescent probes. We describe the facile synthesis of three probes that retain similar antibacterial profiles to the parent vancomycin antibiotic. We demonstrate the versatility of these probes for the detection and visualisation of Gram-positive bacteria by a range of methods, including plate reader quantification, flow cytometry analysis, high-resolution microscopy imaging, and single cell microfluidics analysis. In parallel, we demonstrate their utility in measuring outer-membrane permeabilisation of Gram-negative bacteria. The probes are useful tools that may facilitate detection of infections and development of new antibiotics.

Metals to combat antimicrobial resistance.

Bacteria, similar to most organisms, have a love-hate relationship with metals: a specific metal may be essential for survival yet toxic in certain forms and concentrations. Metal ions have a long history of antimicrobial activity and have received increasing attention in recent years owing to the rise of antimicrobial resistance. The search for antibacterial agents now encompasses metal ions, nanoparticles and metal complexes with antimicrobial activity ('metalloantibiotics'). Although yet to be advanced to the clinic, metalloantibiotics are a vast and underexplored group of compounds that could lead to a much-needed new class of antibiotics. This Review summarizes recent developments in this growing field, focusing on advances in the development of metalloantibiotics, in particular, those for which the mechanism of action has been investigated. We also provide an overview of alternative uses of metal complexes to combat bacterial infections, including antimicrobial photodynamic therapy and radionuclide diagnosis of bacterial infections.

Use of Antiviral Agents and other Therapies for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic led to a remarkably rapid development of a range of effective prophylactic vaccines, including new technologies that had not previously been approved for human use. In contrast, the development of new small molecule antiviral therapeutics has taken years to produce the first approved drugs specifically targeting severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), with the intervening years filled with attempts to repurpose existing drugs and the development of biological therapeutics. This review will discuss the reasons behind this variation in timescale and provide a survey of the many new treatments that are progressing through the clinical pipeline.

In Vitro Activity of Vancapticin MCC5145 against Methicillin-Resistant Staphylococcus aureus from Periprosthetic Joint Infection.

MRSA periprosthetic 1 joint infection (PJI) can be challenging to treat due to biofilm formation, alongside sometimes limited vancomycin activity (1-3).….

A fluorescently labelled quaternary ammonium compound (NBD-DDA) to study resistance mechanisms in bacteria.

Quaternary ammonium compounds (QACs) are widely used as active agents in disinfectants, antiseptics, and preservatives. Despite being in use since the 1940s, there remain multiple open questions regarding their detailed mode-of-action and the mechanisms, including phenotypic heterogeneity, that can make bacteria less susceptible to QACs. To facilitate studies on resistance mechanisms towards QACs, we synthesized a fluorescent quaternary ammonium compound, namely N-dodecyl-N,N-dimethyl-[2-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]ethyl]azanium-iodide (NBD-DDA). NBD-DDA is readily detected by flow cytometry and fluorescence microscopy with standard GFP/FITC-settings, making it suitable for molecular and single-cell studies. As a proof-of-concept, NBD-DDA was then used to investigate resistance mechanisms which can be heterogeneous among individual bacterial cells. Our results reveal that the antimicrobial activity of NBD-DDA against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa is comparable to that of benzalkonium chloride (BAC), a widely used QAC, and benzyl-dimethyl-dodecylammonium chloride (BAC12), a mono-constituent BAC with alkyl-chain length of 12 and high structural similarity to NBD-DDA. Characteristic time-kill kinetics and increased tolerance of a BAC tolerant E. coli strain against NBD-DDA suggest that the mode of action of NBD-DDA is similar to that of BAC. As revealed by confocal laser scanning microscopy (CLSM), NBD-DDA is preferentially localized to the cell envelope of E. coli, which is a primary target of BAC and other QACs. Leveraging these findings and NBD-DDA's fluorescent properties, we show that reduced cellular accumulation is responsible for the evolved BAC tolerance in the BAC tolerant E. coli strain and that NBD-DDA is subject to efflux mediated by TolC. Overall, NBD-DDA's antimicrobial activity, its fluorescent properties, and its ease of detection render it a powerful tool to study resistance mechanisms of QACs in bacteria and highlight its potential to gain detailed insights into its mode-of-action.

Metal Complexes as Antifungals? From a Crowd-Sourced Compound Library to the First In Vivo Experiments.

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 µM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection.

Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the in vitro and in vivo profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi. Derivatives with monocyclic side chains were selective against Mycobacterium tuberculosis and were able to reduce the bacterial load when dosed orally in mice. We demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in M. tuberculosis. Oral administration of compounds with extended biaryl side chains (73 and 74) was effective in suppressing infection in an acute T. cruzi-infected murine model. These findings demonstrate that active nitroimidazopyrazinones have potential to be developed as orally available clinical candidates against both tuberculosis and Chagas disease.

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

N-Alkyl-2-Quinolonopyrones Demonstrate Antimicrobial Activity against ESKAPE Pathogens Including Staphylococcus aureus.

Antibiotic resistance has grown significantly in the last three decades, while research and development of new antibiotic classes has languished. Therefore, new chemical frameworks for the control of microbial behavior are urgently required. This study presents a novel suite of compounds, based on a tricyclic 4-hydroxy-2H-pyrano[3,2-c]quinoline-2,5(6H)-dione core, with significant antibiotic activity against the ESKAPE pathogens Staphylococcus aureus and Enterococcus faecalis and the "accidental pathogen" Staphylococcus epidermidis. A potent analogue with an N-heptyl-9-t-Bu substitution pattern emerged as a hit with MIC levels ≤2 µg/mL across four strains of MRSA. In addition, the same compound proved highly potent against Enterococcus spp. (0.25 µg/mL).

Leveraging the potential of silver nanoparticles-based materials towards sustainable water treatment.

Increasing demand of pure and accessible water and improper disposal of waste into the existing water resources are the major challenges for sustainable development. Nanoscale technology is an effective approach that is increasingly being applied to water remediation. Compared to conventional water treatment processes, silver nanotechnology has been demonstrated to have advantages due to its anti-microbial and oligodynamic (biocidal) properties. This review is focused on environmentally friendly green syntheses of silver nanoparticles (AgNPs) and their applications for the disinfection and microbial control of wastewater. A bibliometric keyword analysis is conducted to unveil important keywords and topics in the utilisation of AgNPs for water treatment applications. The effectiveness of AgNPs, as both free nanoparticles (NPs) or as supported NPs (nanocomposites), to deal with noxious pollutants like complex dyes, heavy metals as well as emerging pollutants of concern is also discussed. This knowledge dataset will be helpful for researchers to identify and utilise the distinctive features of AgNPs and will hopefully stimulate the development of novel solutions to improve wastewater treatment. This review will also help researchers to prepare effective water management strategies using nano silver-based systems manufactured using green chemistry.

Fast bacterial growth reduces antibiotic accumulation and efficacy.

Phenotypic variations between individual microbial cells play a key role in the resistance of microbial pathogens to pharmacotherapies. Nevertheless, little is known about cell individuality in antibiotic accumulation. Here, we hypothesise that phenotypic diversification can be driven by fundamental cell-to-cell differences in drug transport rates. To test this hypothesis, we employed microfluidics-based single-cell microscopy, libraries of fluorescent antibiotic probes and mathematical modelling. This approach allowed us to rapidly identify phenotypic variants that avoid antibiotic accumulation within populations of Escherichia coli, Pseudomonas aeruginosa, Burkholderia cenocepacia, and Staphylococcus aureus. Crucially, we found that fast growing phenotypic variants avoid macrolide accumulation and survive treatment without genetic mutations. These findings are in contrast with the current consensus that cellular dormancy and slow metabolism underlie bacterial survival to antibiotics. Our results also show that fast growing variants display significantly higher expression of ribosomal promoters before drug treatment compared to slow growing variants. Drug-free active ribosomes facilitate essential cellular processes in these fast-growing variants, including efflux that can reduce macrolide accumulation. We used this new knowledge to eradicate variants that displayed low antibiotic accumulation through the chemical manipulation of their outer membrane inspiring new avenues to overcome current antibiotic treatment failures.

Bacteria can cause an array of diseases ranging from mildly inconvenient to deadly. In fact, every year around the world, five million people succumb to a bacterial infection. Antibiotics can kill bacteria or stop their growth, but many bacterial species are now able to evade these drugs. To be efficient, most antibiotics first need to get inside a bacterium; there, they accumulate until they reach the concentration they need to act. Often, the drugs make their way through channel-like structures ('pores') studded through the external membranes of bacteria and which control the passage of molecules in and out of cells. Resistance usually emerges when genetic changes provide the microorganism with an advantage against antibiotics, or when the microorganism performs the biochemical reactions necessary for life at a slower pace. In contrast, Lapinska, Pagliara et al. decided to examine how genetically similar Escherichia coli bacteria which differed in their growth rate would fare against antibiotics. The drug targeted ribosomes, the machinery that produces proteins in a cell. A combination of techniques was used to follow individual cells, revealing that fast-growing variants better managed to survive. A closer look showed that bacteria which were growing quickly had a surplus of ribosomes, which then produced more pores that could pump the antibiotic out the cell. Next, Lapinska, Pagliara et al. exposed the bacteria to both the antibiotic and a compound that weakens bacterial membrane; this erased the advantage shown by the fast-growing variants. Overall, this work gives a finer understanding of the mechanisms that underlie antibiotic resistance, which could help pave the way to new strategies to combat harmful bacteria.