Polycations, mimicking activity of antibacterial peptides, belong to an important class of molecules investigated as a support or as an alternative to antibiotics. In this work, studies of modified ...linear amphiphilic statistical polymethyloxazoline (PMOX) and polyethyleneimine copolymers (PMOX_PEI) series are presented. Variation of PEI content in the structure results in controllable changes of polymeric aggregates zeta potential. The structure with the highest positive charge shows the best antimicrobial activity, well visible in tests against model Gram‐positive and Gram‐negative bacteria, fungi, and mycobacterium strains. The polymer toxicity is evaluated with MTT and hemolysis assay as a reference. Quartz crystal microbalance (QCM‐D) is used to investigate interaction between polycations and a model lipid membrane. Polymer activity correlates well with molecular structure, showing that amphiphilic component is altering polymer behavior in contact with the lipid bilayer.
Series of modified linear amphiphilic statistical polymethyloxazoline (PMOX) and polyethyleneimine copolymers (PMOX_PEI) are obtained by the variation in PEI repeating units content allowing for control over zeta potential of the polymeric aggregates. Performed modification alters antimicrobial, hemolytic, and toxicity activity and is reflected in contact with lipid bilayer as seen in quartz crystal microbalance (QCM) experiments.
The activity of several halogenated copper (II) complexes of 4-chloro-3-nitrophenylthiourea derivatives has been tested against Mycobacterium tuberculosis strains and strains of non-tuberculous ...mycobacteria. The compounds were 2–16 times more potent than current TB-drugs against multidrug-resistant M. tuberculosis 210. The 3,4-dichlorophenylthiourea complex (5) was equipotent to ethambutol (EMB) towards M. tuberculosis H37Rv and 192 strains. All derivatives acted 2–8 times stronger than isoniazid (INH) against nontuberculous isolates. In the presence of chosen coordinates, the 2–64 times reduction of MIC values of standard drugs was denoted. The synergistic interaction was found between the complex 4 and rifampicin (RMP), and additivity of 1–5, 8 in pairs with EMB and/or streptomycin (SM) against M. tuberculosis 800 was established. All coordination compounds in combination with at least one drug showed additive activity towards both H37Rv and 192 isolates. In 67% incidences of indifference, the individual MIC of a drug decreased 2-16-fold. One can conclude that the novel thiourea chelates described here are potent hits for further developments of new agents against tuberculosis.
An alarming increase of antibiotic resistance among pathogens creates an urgent need to develop new antimicrobial agents. Many reported polycations show high antimicrobial activity along with low ...hemolytic activity. Unfortunately, most of those molecules remain highly cytotoxic against various mammalian cells. In this work, a systematic study on the impact of triethylene glycol monomethyl ether side groups (short polyethylene glycol (PEG) analog) on antimicrobial, hemolytic, and cytotoxic properties of novel amphiphilic ionenes is presented. A detailed description of synthesis, leading to well‐defined alternating polymers, which differ in structural elements responsible for hydrophilicity (PEG) and hydrophobicity (alkyl chain), is presented. Obtained results show that the PEG moiety and fine‐tuned hydrophilic‐lipophilic balance of ionenes synergistically lead to low cytotoxic, low hemolytic molecules with high activity against S. aureus, including methicillin‐resistant strains (MRSA). Additionally, the results of mechanistic studies on bacterial cells and fluorescently labeled liposomes are also discussed.
Two series of novel quaternary ammonium ionenes—with and without short polyethylene glycol (PEG) moiety—are obtained to study the influence of an addition hydrophilic and noncharged side group on the biological activity of ionenes. The incorporation of PEG decreases both antimicrobial and cytotoxic properties of ionenes; overall selectivity is improved for two of studied polycations.
Cationic polymers have been extensively investigated as a potential replacement for traditional antibiotics. Here, we examined the effect of molecular weight (MW) on the antimicrobial, cytotoxic, and ...hemolytic activity of linear polytrimethylenimine (L-PTMI). The results indicate that the biological activity of the polymer sharply increases as MW increases. Thanks to a different position of the antibacterial activity and toxicity thresholds, tuning the MW of PTMI allows one to achieve a therapeutic window between antimicrobial activity and toxicity concentrations. L-PTMI presents significantly higher antimicrobial activity against model microorganisms than linear polyethylenimine (L-PEI) when polymers with a similar number of repeating units are compared. For the derivatives of L-PTMI and L-PEI, obtained through
-monomethylation and partial
-dimethylation of linear polyamines, the antimicrobial activity and toxicity were both reduced; however, resulting selectivity indices were higher. Selected materials were tested against clinical isolates of pathogens from the ESKAPE group and
, revealing good antibacterial properties of L-PTMI against antibiotic-resistant strains of Gram-positive and Gram-negative bacteria but limited antibacterial properties against
.
Patients with cystic fibrosis are predisposed to chronic respiratory tract infections caused by Pseudomonas aeruginosa. As the disease progresses, the microorganism diversifies into genotypically and ...phenotypically different strains which may coexist in the patient's airways for years. Adaptation of the microorganism to the airways of patients with cystic fibrosis probably occurs in response to the host's airway environment, the elements of the immune system and antibiotic therapy. Due to the chronic persistence of the microorganism in the airways, a comprehensive molecular analysis was conducted. The analysis included 120 strains isolated from 10 adult cystic fibrosis patients with chronic P. aeruginosa infection. The aim of the study was to analyze the molecular patterns of P. aeruginosa strains and to trace their transmission in the population of cystic fibrosis patients, as well as to study a relationship of the disease with specific phenotypic features. In the research, a genotypic analysis of P. aeruginosa was performed using pulsed-field gel electrophoresis. The results of a number of phenotypic features of the strains were added to the outcomes of the molecular studies. As a result, 28 different genotypes were distinguished. The study also showed cross-transmission of strains between patients. 3 transmissible clusters were identified, including IG1 and IG2 clusters with 9 strains of P. aeruginosa each, obtained from 2 patients and IG3 cluster with 6 strains of P. aeruginosa isolated from 3 patients. Moreover, it was found that in some patients, several unrelated strains of P. aeruginosa may transiently or permanently infect the respiratory tract. A comprehensive understanding of the P. aeruginosa adaptation may help to develop more effective antimicrobial therapies and to identify new targets for future drugs in order to prevent progression of the infection to chronic stages.
Implants made of ceramic and metallic elements, which are used in dentistry, may either promote or hinder the colonization and adhesion of bacteria to the surface of the biomaterial to varying ...degrees. The increased interest in the use of dental implants, especially in patients with chronic systemic diseases such as cystic fibrosis (CF), is caused by an increase in disease complications. In this study, we evaluated the differences in the in vitro biofilm formation on the surface of biomaterials commonly used in dentistry (Ti-6Al-4V, cobalt-chromium alloy (CoCr), and zirconia) by
isolated from patients with CF. We demonstrated that
adherence and growth depends on the type of material used and its surface topography. Weaker bacterial biofilm formation was observed on zirconia surfaces compared to titanium and cobalt-chromium alloy surfaces. Moreover, scanning electron microscopy showed clear differences in bacterial aggregation, depending on the type of biomaterial used. Over the past several decades,
strains have developed several mechanisms of resistance, especially in patients on chronic antibiotic treatment such as CF. Therefore, the selection of an appropriate implant biomaterial with limited microorganism adhesion characteristics can affect the occurrence and progression of oral cavity infections, particularly in patients with chronic systemic diseases.
In many countries tuberculosis (TB) remains a highly prevalent disease and a major contributor to infectious disease mortality. The fight against TB requires surveillance of the population of strains ...circulating worldwide and the analysis of the prevalence of certain strains in populations. Nowadays, whole genome sequencing (WGS) allows for accurate tracking of TB transmission. Currently, there is a lack of a comprehensive summary of the characteristics of TB outbreaks.
We systematically analyzed studies reporting TB outbreaks worldwide, monitored through WGS of Mycobacterium tuberculosis. We 1) mapped the reported outbreaks from 2011- 2020, 2) estimated the average size of the outbreaks, 3) indicated genetic lineages causing the outbreaks, and 4) determined drug-resistance patterns of M. tuberculosis strains involved in the outbreaks.
Most data originated from Europe, Asia, and North America. We found that TB outbreaks were reported throughout the globe, on all continents, and in countries with both high and low incidences. The detected outbreaks contained a median of five M. tuberculosis isolates. Most strains causing the outbreaks belonged to lineage four, more rarely to lineage two. Reported outbreak isolates were often drug resistant.
We conclude that more WGS surveillance of M. tuberculosis outbreaks is needed. Globally standardized procedures might improve the control of M. tuberculosis infections.
A series of thirty eight novel compounds are synthesised and evaluated for their anti-TB activity. Amongst them, compound 7j exhibited very good anti-TB activity with MIC 6.16μM and SI was >36. In ...addition, docking studies for all compounds were performed on mycobacterial pantothenate synthase enzyme and interaction pattern of the compound 7j was analysed. Display omitted
•38 novel benzodisoxazoles were synthesised and evaluated for anti-TB activity.•4 analogues (MIC<30μM) exhibited very good anti-TB activity against 3 MTB strains.•In vitro cytotoxicity studies of the most active compounds were analysed.•All compounds docking scores displayed in between −7.1 and −10.7kcal/mol.•Compound 7j was docking with mycobacterial PS enzyme (4MQ6.pdb).
A series of thirty eight novel 3-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl/1,4-diazepan-1-yl)benzodisoxazole and 1-(4-(benzodisoxazol-3-yl)piperazin-1-yl/1,4-diazepan-1-yl)-2-(1H-indol-3-yl)substituted-1-one analogues were synthesised, characterised using various analytical techniques and evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two ‘wild’ strains Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 6.16 to >200μM. Among the tested compounds, 7i, 7y and 7z exhibited moderate activity (MIC=24.03–29.19μM) and 7j exhibited very good anti-tubercular activity (MIC=6.16μM). Furthermore, 7i, 7j, 7y and 7z were found to be non-toxic against mouse macrophage cell lines when screened for toxicity. All the synthesised compounds were docked to pantothenate synthetase enzyme site to know deferent binding interactions with the receptor.
The Mycobacterium avium complex (MAC) comprises a widespread group of slowly-growing bacteria from the Mycobacteriaceae. These bacteria are responsible for opportunistic infections in humans and ...animals, including farm animals. The aim of the study was to determine whether it is possible to predict the presence of M. avium in pig lymph nodes based on the size and type of lesions found during post-mortem examination at a slaughterhouse. Lymph nodes were collected from 10,600 pigs subjected to such post-mortem examination. The nodes were classified with regard to their quality, and the number of tuberculosis-like lesions; following this, 86 mandibular lymph nodes with lesions and 113 without visible macroscopic lesions were selected for further study. Cultures were established on Löwenstein-Jensen and Stonebrink media, and a commercial GenoType Mycobacterium CM test was used to identify and differentiate M. avium species. The prevalence of M. avium was 56.98% in the lymph nodes with lesions and 19.47% in the unchanged ones. Statistical analysis indicated that visual assessment of lesions in the mandibular lymph nodes, in particular the number of tuberculous lesions, is a highly-efficient diagnostic tool. Similar results were obtained for estimated percentage area affected by the lesion, i.e. the ratio of the changed area of the lymph node in cross-section to the total cross-sectional area of the lymph node; however, this method is more laborious and its usefulness in slaughterhouse conditions is limited. By incising the lymph nodes and assessing the number of tuberculosis-like lesions, it is possible to limit the inclusion of meat from pigs infected with M. avium into the human food chain.
Abstract
In this work, we investigated the antitubercular properties of Ciprofloxacin derivatives conjugated with menthol and thymol moieties. For the sixteen derivatives, we established minimal ...inhibitory concentrations (MIC) using isolates of
Mycobacterium tuberculosis
that were resistant or susceptible to other antibiotics. For the most potent compound 1‐cyclopropyl‐6‐fluoro‐7‐{4‐6‐((1R,2S,5R)‐2‐isopropyl‐5‐methylcyclohexyloxy)‐6‐oxohexylpiperazin‐1‐yl}‐4‐oxo‐1,4‐dihydroquinoline‐3‐carboxylic acid (
6
), we determined fractional inhibitory concentration index (FICI) values to confirm antibacterial susceptibility and synergistic effects with other reference drugs. In addition, chromatographic studies of all the derivatives demonstrated a significant three to four-fold increase in lipophilicity and affinity to phospholipids compared to Ciprofloxacin. Finally, we conducted structure-based studies of the investigated compounds using molecular docking and taking into account protein target mutations associated with fluoroquinolone resistance. In summary, our findings indicate that the investigated compounds possess tuberculostatic properties, with some showing similar or even better activity against resistant strains compared to reference drugs. Increased lipophilicity and affinity to phospholipids of the new derivatives can offer several advantages for new drug candidates, beyond just improved cell membrane penetration. However, further studies are needed to fully understand their safety, efficacy, and mechanism of action.
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