Antibacterial and antibiofilm agents in the group of xanthone derivatives with piperazine moiety active against drug-resistant Helicobacter pylori strains.

Helicobacter pylori (H. pylori) cause chronic inflammation of the gastric mucosa which can lead to epithelial atrophy and metaplasia resulting in peptic ulcer disease and gastric cancer. The increasing resistance of H. pylori to antibiotics and chemotherapeutics used to treat the infection is a serious problem. However, it has been confirmed that the introduction of effective anti-H. pylori therapy can prevent the progression to cancerous changes. This problem calls for the search for new and effective therapies. Xanthones are a group of compounds with extensive biological activities, including antibacterial activity, also against H. pylori. Addressing this issue, the aim of the study was to evaluate the potential of a group of 13 xanthone derivatives against susceptible and resistant H. pylori strains. Moreover, our objective was to conduct tests aimed at determining their ability to inhibit biofilm formation. The antimicrobial evaluation revealed that benzylpiperazine coupled at the C-2 position to xanthone (compounds C11 and C12) had good selective bacteriostatic activity against reference and clinical H. pylori strains (MBC/MIC ratio >4) but with no activity against other bacteria such as Staphylococcus aureus, Escherichia coli, and Lactobacillus paracasei. Analysis of the activity of compounds C11 and C12 against the biofilm formed by H. pylori strain ATCC 700684, and the clinical strain showed that these compounds caused a significant reduction in the amount of biofilm produced (5-20×). Moreover, cell viability analysis confirmed a 3-4× reduction in the viability of cells forming biofilm after treatment with C11 and C12. Finally,both compounds did not impair human fibroblast viability at tested concentrations and were not mutagenic in the Ames test. Therefore, they could be promising leads as antibacterial candidates for multidrug-resistant strains of H. pylori.

[Effectiveness of curcumin as photodynamic therapy for endodontic procedures: a narrative review]. / Efectividad de la curcumina como terapia fotodinámica para los procedimientos de endodoncia: una revisión narrativa.

Introduction: Endodontic therapy is performed by biomechanical preparation and intracanal medication; however, residual bacteria can be compromised due to their ability to adhere to the root canal walls. Therefore, photodynamic therapy has gained popularity because of its good ability to prevent and eradicate microbial infections by using a light-activated dye. Objective: Analyze and to update the information on the effect of curcumin in photodynamic therapy in root canal treatment. Material and Methods: A literature search was carried out in PubMed/MEDLINE, Scopus, Ebsco, Science Direct, and LILACS databases using the keywords "curcumin", "turmeric", "photodynamic", "photochemotherapy", "photoradiation", "photoactivated disinfection", "root canal disinfection", "root canal therapy", "endodontics" in both Spanish and English, from 2018 to 2023. Results: Information from the last five years was collected with the aim of updating the study topic. 749 articles were examined using inclusion and exclusion criteria, of which only 50 met these criteria and were analyzed. Current studies show the effects of therapy on the contamination of the root canal biofilm with E. faecalis, demonstrating that photoactivated curcumin promotes the disruption of the biofilm and reduction of Colony-Forming Units. Conclusions: Curcumin as a photosensitizer demonstrates a potential antibacterial effect significantly decreasing the viability of microbial cells and the vitality of biofilms.

Phytochemical characterisation of dichloromethane and methanolic extracts of the Ziziphora tenuior leaves and evaluation of their antioxidant and antibacterial activities.

Medicinal plants, known for their antibacterial phytocompounds and secondary metabolites, offer promising potential in combating antibiotic-resistant bacteria. This study aimed to perform a phytochemical analysis of the methanol and dichloromethane extracts obtained from Ziziphora tenuior leaves using GC-MS. Furthermore, the antioxidant activity of the extracts was evaluated through the DPPH assay. And, their antibacterial activity was assessed against S. aureus, E. coli, methicillin-resistant S. aureus, and vancomycin-resistant enterococcus (VRE) bacterial strains. Based on the results 90-92% of these extracts consisted of phytocompounds with pharmaceutical properties. Of these, 5-methyl- 2-(1-methylethylidele), Cyclohexanone (Pulegone; C10H16O) comprised the highest percentage of the extracts, constituting 62% of methanolic extract and 81% of dichloromethane extract. Also, both methanolic and dichloromethane extracts showed potent antioxidant activity with IC50 of 277.6 µg/ml and 49.6 µg/ml, respectively. Moreover, these extracts demonstrated considerable antibacterial activity against the tested pathogens, especially against S. aureus and VRE.

Current View on Major Natural Compounds Endowed with Antibacterial and Antiviral Effects.

Nowadays, infectious diseases of bacterial and viral origins represent a serious medical problem worldwide. In fact, the development of antibiotic resistance is responsible for the emergence of bacterial strains that are refractory even to new classes of antibiotics. Furthermore, the recent COVID-19 pandemic suggests that new viruses can emerge and spread all over the world. The increase in infectious diseases depends on multiple factors, including malnutrition, massive migration of population from developing to industrialized areas, and alteration of the human microbiota. Alternative treatments to conventional antibiotics and antiviral drugs have intensively been explored. In this regard, plants and marine organisms represent an immense source of products, such as polyphenols, alkaloids, lanthipeptides, and terpenoids, which possess antibacterial and antiviral activities. Their main mechanisms of action involve modifications of bacterial cell membranes, with the formation of pores, the release of cellular content, and the inhibition of bacterial adherence to host cells, as well as of the efflux pump. Natural antivirals can interfere with viral replication and spreading, protecting the host with the enhanced production of interferon. Of note, these antivirals are not free of side effects, and their administration to humans needs more research in terms of safety. Preclinical research with natural antibacterial and antiviral compounds confirms their effects against bacteria and viruses, but there are still only a few clinical trials. Therefore, their full exploitation and more intensive clinical studies represent the next steps to be pursued in this area of medicine.

Synthesis, Antimicrobial, Molecular Docking Against Bacterial and Fungal Proteins and In Silico Studies of Glucopyranoside Derivatives as Potent Antimicrobial Agents.

Carbohydrate derivatives play a crucial roles in biochemical and medicinal research, especially in the fields of chemistry and biochemistry. From this perspective, the present study was designed to explore the synthesis of methyl α-D-glucopyranoside derivatives (1-8), focusing on their efficacy against bacterial and fungal inhibition. The structure of the synthesized compounds was ascertained using FTIR, 1H-NMR, 13C-NMR, mass and elemental analyses. Antimicrobial screening revealed strong antifungal properties, with compound 7 exhibiting minimum inhibitory concentrations (MICs) ranging from 16-32 µg/L and minimum bactericidal concentrations (MBCs) ranging from 64-128 µg/L. Incorporating decanoyl acyl groups at C-2 and C-3 of (7) significantly improved the efficacy against bacteria and fungi. Structure-activity relationship (SAR) analysis indicated that adding nonanoyl and decanoyl groups to the ribose moiety enhanced potency against both bacterial and fungal strains. Computational methods, including molecular docking, density functional theory (DFT), Petra, Osiris, Molinspiration (POM) evaluation, and molecular dynamics (MD) simulations, were used to assess the efficacy of these derivatives. Compounds 6 and 7, which presented nonanoyl and decanoyl substituents, demonstrated greater efficacy. In addition, DFT studies identified compound 8 as possessing ideal electronic properties. Molecular docking revealed that compound 8 exhibits exceptional binding affinities to bacterial proteins, conferring potent antibacterial and antifungal activities. In addition, pharmacokinetic optimization via POM analysis highlighted compounds 1 and 2 as promising bioavailable drugs with minimal toxicity. Molecular dynamics simulations confirmed the stability of the 2-S. aureus complex, revealing the therapeutic potential of compounds 2 and 8. Future experiments are required to validate their efficacy for pharmaceutical development. The integration of in vitro and in silico methods, including DFT anchoring dynamics and molecular dynamics simulations, provides a solid framework for the advancement of effective anti-infective drugs.

Exploring the Darobactin Class of Antibiotics: A Comprehensive Review from Discovery to Recent Advancements.

The prevalence of antimicrobial resistance in Gram-negative bacteria poses a greater challenge due to their intrinsic resistance to many antibiotics. Recently, darobactins have emerged as a novel class of antibiotics originating from previously unexplored Gram-negative bacterial species such as Photorhabdus, Vibrio, Pseudoalteromonas and Yersinia. Darobactins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) class of antibiotics, exhibiting selective activity against Gram-negative bacteria. They target the ß-barrel assembly machinery (BAM), which is crucial for the maturation and insertion of outer membrane proteins in Gram-negative bacteria. The dar operon in the producer's genome encodes for the synthesis of darobactins, which are characterized by a fused ring system connected via an alkyl-aryl ether linkage (C-O-C) and a C-C cross-link. The enzyme DarE, using the radical S-adenosyl-l-methionine (rSAM), facilitates the formation of these bonds. Biosynthetic manipulation of the darobactin gene cluster, along with its expression in a surrogate host, has enabled access to diverse darobactin analogues with variable antibiotic activities. Recently, two independent research groups successfully achieved the total synthesis of darobactin, employing Larock heteroannulation to construct the bicyclic structure. This paper presents a comprehensive review of darobactins, encompassing their discovery through to the most recent advancements.

Plantago major and Plantago lanceolata Exhibit Antioxidant and Borrelia burgdorferi Inhibiting Activities.

Lyme disease, caused by Borrelia burgdorferi sensu lato infection, is the most widespread vector-borne illness in the Northern Hemisphere. Unfortunately, using targeted antibiotic therapy is often an ineffective cure. The antibiotic resistance and recurring symptoms of Lyme disease are associated with the formation of biofilm-like aggregates of B. burgdorferi. Plant extracts could provide an effective alternative solution as many of them exhibit antibacterial or biofilm inhibiting activities. This study demonstrates the therapeutic potential of Plantago major and Plantago lanceolata as B. burgdorferi inhibitors. Hydroalcoholic extracts from three different samples of each plant were first characterised based on their total concentrations of polyphenolics, flavonoids, iridoids, and antioxidant capacity. Both plants contained substantial amounts of named phytochemicals and showed considerable antioxidant properties. The major non-volatile constituents were then quantified using HPLC-DAD-MS analyses, and volatile constituents were quantified using HS-SPME-GC-MS. The most prevalent non-volatiles were found to be plantamajoside and acteoside, and the most prevalent volatiles were ß-caryophyllene, D-limonene, and α-caryophyllene. The B. burgdorferi inhibiting activity of the extracts was tested on stationary-phase B. burgdorferi culture and its biofilm fraction. All extracts showed antibacterial activity, with the most effective lowering the residual bacterial viability down to 15%. Moreover, the extracts prepared from the leaves of each plant additionally demonstrated biofilm inhibiting properties, reducing its formation by 30%.

An injectable magnesium-coordinated phosphate chitosan-based hydrogel loaded with vancomycin for antibacterial and osteogenesis in the treatment of osteomyelitis.

Microbial infections of bones, particularly after joint replacement surgery, are a common occurrence in clinical settings and often lead to osteomyelitis (OM). Unfortunately, current treatment approaches for OM are not satisfactory. To address this issue, this study focuses on the development and evaluation of an injectable magnesium oxide (MgO) nanoparticle (NP)-coordinated phosphocreatine-grafted chitosan hydrogel (CMPMg-VCM) loaded with varying amounts of vancomycin (VCM) for the treatment of OM. The results demonstrate that the loading of VCM does not affect the formation of the injectable hydrogel, and the MgO-incorporated hydrogel exhibits anti-swelling properties. The release of VCM from the hydrogel effectively kills S.aureus bacteria, with CMPMg-VCM (50) showing the highest antibacterial activity even after prolonged immersion in PBS solution for 12 days. Importantly, all the hydrogels are non-toxic to MC3T3-E1 cells and promote osteogenic differentiation through the early secretion of alkaline phosphatase and calcium nodule formation. Furthermore, in vivo experiments using a rat OM model reveal that the CMPMg-VCM hydrogel effectively kills and inhibits bacterial growth, while also protecting the infected bone from osteolysis. These beneficial properties are attributed to the burst release of VCM, which disrupts bacterial biofilm, as well as the release of Mg ions and hydroxyl by the degradation of MgO NPs, which inhibits bacterial growth and prevents osteolysis. Overall, the CMPMg-VCM hydrogel exhibits promising potential for the treatment of microbial bone infections.

Plant Extract in the Control of Poultry Omphalitis.

Bacteria continue to disrupt poultry production and can cause resistant and persistent yolk sac infections to prevention efforts, known as omphalitis, resulting in poultry death. This literature review aims to demonstrate how plant extracts can help combat omphalitis in poultry. The Google Scholar database served as a resource for retrieving pertinent literature covering a wide range of search terms relevant to the scope of the research. The search strategy involved a combination of terms such as antimicrobials, chick embryo, omphalitis, plant extracts, poultry nutrition, and sanitization. The potential of plant extracts in preventing or treating infections in poultry, especially omphalitis, is mainly due to their antibacterial and safety properties. Sanitization and direct delivery of plant extracts to the internal contents of eggs, feed, or water are cutting-edge interventions to reduce the bacterial load in eggs and poultry, minimizing infection rates. For example, these interventions may include advanced treatment technologies or precise delivery systems focused on disease prevention in poultry.

Rapid, DNA-induced interface swapping by DNA gyrase.

DNA gyrase, a ubiquitous bacterial enzyme, is a type IIA topoisomerase formed by heterotetramerisation of 2 GyrA subunits and 2 GyrB subunits, to form the active complex. DNA gyrase can loop DNA around the C-terminal domains (CTDs) of GyrA and pass one DNA duplex through a transient double-strand break (DSB) established in another duplex. This results in the conversion from a positive (+1) to a negative (-1) supercoil, thereby introducing negative supercoiling into the bacterial genome by steps of 2, an activity essential for DNA replication and transcription. The strong protein interface in the GyrA dimer must be broken to allow passage of the transported DNA segment and it is generally assumed that the interface is usually stable and only opens when DNA is transported, to prevent the introduction of deleterious DSBs in the genome. In this paper, we show that DNA gyrase can exchange its DNA-cleaving interfaces between two active heterotetramers. This so-called interface 'swapping' (IS) can occur within a few minutes in solution. We also show that bending of DNA by gyrase is essential for cleavage but not for DNA binding per se and favors IS. Interface swapping is also favored by DNA wrapping and an excess of GyrB. We suggest that proximity, promoted by GyrB oligomerization and binding and wrapping along a length of DNA, between two heterotetramers favors rapid interface swapping. This swapping does not require ATP, occurs in the presence of fluoroquinolones, and raises the possibility of non-homologous recombination solely through gyrase activity. The ability of gyrase to undergo interface swapping explains how gyrase heterodimers, containing a single active-site tyrosine, can carry out double-strand passage reactions and therefore suggests an alternative explanation to the recently proposed 'swivelling' mechanism for DNA gyrase (Gubaev et al., 2016).

Simultaneous determination of 68 antimicrobial compounds in pigs oral fluid by ultra-high performance liquid chromatography-tandem mass spectrometry.

Improper use of antimicrobials in veterinary medicine can lead to residues in food of animal origin. Post-mortem monitoring of antibiotics in animal products is carried out as part of official EU programmes on food safety and consumer health. Oral fluid testing is a promising surveillance method to monitor appropriate treatment in pigs and to avoid residues in edible tissues. Oral fluid analysis can be implemented in an antibiotic residue control programme, thus preventing economic losses due to meat disposal as a result of drug detection in tissues after the withdrawal period. An analytical method was developed for the analysis of 68 compounds from 12 groups (penicillins, cephalosporins, sulfonamides, macrolides, fluoroquinolones, tetracyclines, aminoglycosides, pleuromutilins, diaminopyrimidines, lincosamides, polypeptides and sulfones) in pig oral fluid. Extraction of antibacterials was performed with 0.5 % formic acid. Analyses were carried out by ultra-high performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-MS/MS) detection. The chromatographic separation was achieved on a Zorbax analytical column (2.1 × 50 mm) with a mobile phase consisting of acetonitrile and heptafluorobutyric acid (HFBA). The total run time was 7 min. The method was validated as a confirmatory method according to the Commission Implementing Regulation (EU) 2021/808. The reliability of the method was verified by testing real samples from pig farms.

Warfarin analogs target disulfide bond-forming enzymes and suggest a residue important for quinone and coumarin binding.

Disulfide bond formation has a central role in protein folding of both eukaryotes and prokaryotes. In bacteria, disulfide bonds are catalyzed by DsbA and DsbB/VKOR enzymes. First, DsbA, a periplasmic disulfide oxidoreductase, introduces disulfide bonds into substrate proteins. Then, the membrane enzyme, either DsbB or VKOR, regenerate DsbA's activity by the formation of de novo disulfide bonds which reduce quinone. We have previously performed a high-throughput chemical screen and identified a family of warfarin analogs that target either bacterial DsbB or VKOR. In this work, we expressed functional human VKORc1 in Escherichia coli and performed a structure-activity-relationship analysis to study drug selectivity between bacterial and mammalian enzymes. We found that human VKORc1 can function in E. coli by removing two positive residues, allowing the search for novel anticoagulants using bacteria. We also found one warfarin analog capable of inhibiting both bacterial DsbB and VKOR and a second one antagonized only the mammalian enzymes when expressed in E. coli. The difference in the warfarin structure suggests that substituents at positions three and six in the coumarin ring can provide selectivity between the bacterial and mammalian enzymes. Finally, we identified the two amino acid residues responsible for drug binding. One of these is also essential for de novo disulfide bond formation in both DsbB and VKOR enzymes. Our studies highlight a conserved role of this residue in de novo disulfide-generating enzymes and enable the design of novel anticoagulants or antibacterials using coumarin as a scaffold.

Synthesis of Bodipy-Tagged Galactoconjugates and Evaluation of Their Antibacterial Properties.

As a development of our research on biocompatible glycoconjugate probes and specifically multi-chromophoric systems, herein, we report the synthesis and early bactericidal tests of two luminescent glycoconjugates whose basic structure is characterized by two boron dipyrromethene difluoride (BODIPY) moieties and three galactoside rings mounted on an oligophenylene ethynylene (OPE) skeleton. BODIPY fluorophores have found widespread application in many branches of biology in the last few decades. In particular, molecular platforms showing two different BODIPY groups have unique photophysical behavior useful in fluorescence imaging. Construction of the complex architecture of the new probes is accomplished through a convergent route that exploits a series of copper-free Heck-Cassar-Sonogashira cross-couplings. The great emergency due to the proliferation of bacterial infections, in conjunction with growing antibiotic resistance, requires the production of new multifunctional drugs and efficient methods for their targeted delivery to control bacteria-associated diseases. Preliminary studies of the glycoconjugate properties as antibacterial agents against representatives of Gram-negative (P. aeruginosa) and Gram-positive (S. aureus) pathogens, which are associated with chronic infections, indicated significant bactericidal activity ascribable to their structural features.

Synthesis, Electronic, and Antibacterial Properties of 3,7-Di(hetero)aryl-substituted Phenothiazinyl N-Propyl Trimethylammonium Salts.

In this study, a library of 3,7-di(hetero)aryl-substituted 10-(3-trimethylammoniumpropyl)10H-phenothiazine salts is prepared. These title compounds and their precursors are reversible redox systems with tunable potentials. The Hammett correlation gives a very good correlation of the first oxidation potentials with σp parameters. Furthermore, the title compounds and their precursors are blue to green-blue emissive. Screening of the salts reveals for some derivatives a distinct inhibition of several pathogenic bacterial strains (Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Aconetobacter baumannii, and Klebsiella pneumoniae) in the lower micromolar range.

Plant antibacterials: The challenges and opportunities.

Nature possesses an inexhaustible reservoir of agents that could serve as alternatives to combat the growing threat of antimicrobial resistance (AMR). While some of the most effective drugs for treating bacterial infections originate from natural sources, they have predominantly been derived from fungal and bacterial species. However, a substantial body of literature is available on the promising antibacterial properties of plant-derived compounds. In this comprehensive review, we address the major challenges associated with the discovery and development of plant-derived antimicrobial compounds, which have acted as obstacles preventing their clinical use. These challenges encompass limited sourcing, the risk of agent rediscovery, suboptimal drug metabolism, and pharmacokinetics (DMPK) properties, as well as a lack of knowledge regarding molecular targets and mechanisms of action, among other pertinent issues. Our review underscores the significance of these challenges and their implications in the quest for the discovery and development of effective plant-derived antimicrobial agents. Through a critical examination of the current state of research, we give valuable insights that will advance our understanding of these classes of compounds, offering potential solutions to the global crisis of AMR. © 2017 Elsevier Inc. All rights reserved.

Treating Pythiosis with Antibacterial Drugs Targeting Protein Synthesis: An Overview.

This review article explores the effectiveness of antibacterial drugs that inhibit protein synthesis in treating pythiosis, a difficult-to-treat infection caused by Pythium insidiosum. The article highlights the susceptibility of P. insidiosum to antibacterial drugs, such as macrolides, oxazolidinones, and tetracyclines. We examine various studies, including in vitro tests, experimental infection models, and clinical case reports. Based on our synthesis of these findings, we highlight the potential of these drugs in managing pythiosis, primarily when combined with surgical interventions. The review emphasizes the need for personalized treatment strategies and further research to establish standardized testing protocols and optimize therapeutic approaches.

A 10-year retrospective study of antibacterial-induced thrombocytopenia in a women and children hospital using China Hospital Pharmacovigilance System and Visual Basic for Applications.

AIMS: We aimed to investigate antibacterial-induced thrombocytopenia using the China Hospital Pharmacovigilance System (CHPS) in conjunction with Visual Basic for Applications (VBA). METHODS: Between September 2011 and December 2022, a 2-phase workflow was employed to identify antibacterial-induced thrombocytopenia, including preliminary screening in phase (I) conducted by CHPS algorithms and causality assessment by trained pharmacists in phase (II) using VBA. The incidence of thrombocytopenia in each antibacterial was calculated, and comparisons were performed between paediatric and adult patients. RESULTS: CHPS algorithms identified 4080 cases from 485 238 admissions (including 223 735 admissions receiving at least 1 antibacterial treatment). After ruling out cases with chemotherapy and abnormal platelet count at admission, 3832 cases were available. Using VBA, pharmacists identified 1039 cases (1246 antibacterial treatments, 28 agents) as potential thrombocytopenia instances (κ = 0.89), with an incidence of 0.46%. All antibacterial treatments correlated temporally with thrombocytopenia. Carbapenems (meropenem 1.77%), glycopeptides (vancomycin 1.55%) and lincosamides (clindamycin 0.44%) were prominent causal groups. The highest incidences of thrombocytopenia in the cephalosporins and penicillins groups were ceftazidime (2.04%) and piperacillin/tazobactam (1.24%), respectively. Among all antibacterial treatments, clindamycin showed the shortest time to onset (TTO), and erythromycin showed the longest TTO. Paediatric patients exhibited a longer TTO (61 vs. 29 h), extended time to nadir (83 vs. 37 h), lower platelet nadir count values (110 vs. 92 × 109/L), and a higher severe case proportion (12.37 vs. 3.86%) when compared with adults. CONCLUSION: Different antibacterial agents exhibit varying incidences of thrombocytopenia, with notable disparities between adults and children in the characteristics of thrombocytopenia.