The alarming rise of bacterial antibiotic resistance requires the development of new compounds. Such compounds, lipophosphonoxins (LPPOs), were previously reported to be active against numerous bacterial species, but serum albumins abolished their activity. Here we describe the synthesis and evaluation of novel antibacterial compounds termed LEGO-LPPOs, loosely based on LPPOs, consisting of a central linker module with two attached connector modules on either side. The connector modules are then decorated with polar and hydrophobic modules. We performed an extensive structure-activity relationship study by varying the length of the linker and hydrophobic modules. The best compounds were active against both Gram-negative and Gram-positive species including multiresistant strains and persisters. LEGO-LPPOs act by first depleting the membrane potential and then creating pores in the cytoplasmic membrane. Importantly, their efficacy is not affected by the presence of serum albumins. Low cytotoxicity and low propensity for resistance development demonstrate their potential for therapeutic use.
Background and Objectives: Given the limited knowledge of antibody responses to COVID-19 and their determinants, we analyzed the relationship between the occurrence of acute-phase symptoms and infection-induced immunoglobulin (Ig) G seropositivity up to 8 months post-symptom onset. Materials and Methods: In this cross-sectional study, 661 middle-aged unvaccinated healthcare workers (HCWs) were interviewed about the presence of symptoms during the acute phase of their previously confirmed COVID-19 and were tested for specific IgG, targeting the spike protein (S1 and S2). The dependence of seropositivity on the symptom occurrence was explored through multiple logistic regression, adjusted for the interval between symptom onset and serology testing, and through classification and regression trees. Results: A total of 551 (83.4%) HCWs showed seropositivity and, inversely, 110 (16.6%) HCWs were seronegative. The chance of IgG seropositivity was increased by dyspnea (odds ratio (OR) 1.48, p < 0.001) and anosmia (OR 1.52, p = 0.021). Fever in HCWs with dyspnea resulted in the highest detected seropositivity rate, and anosmia in HCWs without dyspnea significantly increased the proportion of seropositivity. Conclusion: Clinical manifestation of the acute phase of COVID-19 predisposes to the development of infection-induced antibody responses. The findings can be applied for assessing the long-term protection by IgG, and thus, for creating effective surveillance strategies.
- MeSH
- anosmie MeSH
- COVID-19 * komplikace MeSH
- dyspnoe MeSH
- imunoglobulin G MeSH
- lidé středního věku MeSH
- lidé MeSH
- protilátky virové MeSH
- průřezové studie MeSH
- zdravotnický personál MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The number of antibiotic-resistant bacterial strains is increasing due to the excessive and inappropriate use of antibiotics, which are therefore becoming ineffective. Here, we report an effective way of enhancing and restoring the antibacterial activity of inactive antibiotics by applying them together with a cyanographene/Ag nanohybrid, a nanomaterial that is applied for the first time for restoring the antibacterial activity of antibiotics. The cyanographene/Ag nanohybrid was synthesized by chemical reduction of a precursor material in which silver cations are coordinated on a cyanographene sheet. The antibacterial efficiency of the combined treatment was evaluated by determining fractional inhibitory concentrations (FIC) for antibiotics with different modes of action (gentamicin, ceftazidime, ciprofloxacin, and colistin) against the strains Escherichia coli, Pseudomonas aeruginosa, and Enterobacter kobei with different resistance mechanisms. Synergistic and partial synergistic effects against multiresistant strains were demonstrated for all of these antibiotics except ciprofloxacin, which exhibited an additive effect. The lowest average FICs equal to 0.29 and 0.39 were obtained for colistin against E. kobei and for gentamicin against E. coli, respectively. More importantly, we have experimentally confirmed for the first time, that interaction between the antibiotic's mode of action and the mechanism of bacterial resistance strongly influenced the combined treatment's efficacy.
- MeSH
- antibakteriální látky * chemie farmakologie MeSH
- ciprofloxacin farmakologie MeSH
- Escherichia coli MeSH
- gentamiciny farmakologie MeSH
- kolistin * farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- Pseudomonas aeruginosa MeSH
- synergismus léků MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: Although the incidence of measles has decreased globally since the introduction of regular vaccination, its frequency has increased again in recent years. The study is focused on data from the Olomouc Region in the Czech Republic analyzed in four laboratories. The obtained results were compared with already published data. METHODS: The data were provided by individual laboratories in an anonymized form-age at the time of the examination, sex, and result of test. Samples were collected between June 2018 and September 2019 and evaluated on the scale positive-borderline-negative. RESULTS: A total of 7962 sera samples were evaluated using three different methods-two types of ELISA tests and CLIA. Positive result was issued in a total of 62.6 percent of samples, but the results of individual laboratories varied widely from 55.5 to 70.8 percent. However, the same trend with the highest levels of antibodies in people born before beginning of vaccination was observed. CONCLUSIONS: Data show significantly different results depending on the individual laboratories and the detection kits used. The underestimation of the proportion of positive results can cause problems in selecting individuals for revaccination with a live vaccine, which may fail in weakly positive individuals.
- Publikační typ
- časopisecké články MeSH
(1) Background: The root canal system has complex anatomical and histological features that make it impossible to completely remove all bacteria by mechanical means only; they must be supplemented with disinfectant irrigation. Current disinfectants are unable to eliminate certain microorganisms that persist in the root canal, resulting in treatment failure. At the Institute of Organic Chemistry and Biochemistry, Prague, novel substances with the bactericidal effect, termed lipophosphonoxins (LPPOs), have been discovered. The aim of this pilot study was to investigate the ex vivo effects of second- and third-generation LPPOs on Enterococcus faecalis and compare them with 5% sodium hypochlorite (NaOCl), 0.12% chlorhexidine digluconate, and 17% ethylenediaminetetraacetic acid (EDTA). (2) Methods: The root canal's dentin was used as a carrier for biofilm formation in the extracted human mature mandibular premolars. The samples were filled with cultivation broth and 0.25% glucose with tested solutions. In control samples, only fresh cultivation broth (negative control) and cultivation broth with bacterial suspension (growth control) were used. Each sample was inoculated with E. faecalis CCM4224 except for the negative control, and cultivation was performed. To determine the number of planktonic cells, the sample content was inoculated on blood agar. To evaluate biofilm formation inhibition, samples were placed in tubes with BHI. (3) Results: LPPOs exhibited a reduction in biofilm growth and bacteria comparable to NaOCl, and they were superior to other tested disinfectants. (4) Conclusions: The study results suggest the effect of lipophosphonoxins on E. faecalis CCM 4224 reduces planktonic bacterial cells and inhibits formation of biofilm in root canal samples.
- Publikační typ
- časopisecké články MeSH
Vztah mezi spalničkovým virem a lidským imunitním systémem je značně komplikovaný. Virus buňky imunitního systému potřebuje k navození systémové infekce, ve výsledku je ale imunitními mechanismy z organismu eliminován. Imunitní systém si ale z této interakce odnáší poškození ve formě ztráty části dosud získaného antigenního spektra paměťových buněk. Tato tzv. imunitní amnézie může po dobu minimálně několika měsíců zvyšovat náchylnost k nesouvisejícím infekcím. Účinným nástrojem v boji proti spalničkám je očkování, které vedlo k rozsáhlé eliminaci infekce. V posledních letech ale incidence spalniček vlivem různých faktorů opět narůstá. Pro zvládnutí tohoto trendu je důležité mít přehled o stavu imunity v populaci. Problémem pro jeho získání ale může být variabilita výsledků získaných v různých laboratořích komerčními soupravami různých výrobců, která vyplývá ze srovnání recentně publikovaných séroprevalenčních studií.
The relationship between measles virus and the human immune system is quite complicated. The virus needs cells of the immune system to induce a systemic infection, but as a result it is eliminated from the body by immune mechanisms. However, the immune system takes damage from this interaction in the form of the loss of part of the antigenic spectrum of memory cells acquired so far. This so-called immune amnesia can increase the susceptibility to unrelated infections for at least a few months. Vaccination is the effective tool in the fight against measles, which has led to extensive elimination of the infection. In recent years, however, the incidence of measles has increased again due to various factors. To cope with this trend, it is important to have an overview of the state of immunity in the population. The variability of the results obtained in different laboratories with commercial kits from different manufacturers, which results from a comparison of recently published seroprevalence studies, may be a problem for obtaining it.
- MeSH
- dítě MeSH
- dospělí MeSH
- infekce viry z rodu Morbillivirus imunologie patofyziologie MeSH
- kojenec MeSH
- lidé MeSH
- neutralizační testy metody statistika a číselné údaje MeSH
- novorozenec MeSH
- očkovací schéma MeSH
- protilátky virové analýza MeSH
- séroepidemiologické studie MeSH
- spalničky * epidemiologie imunologie patofyziologie prevence a kontrola MeSH
- vakcína proti spalničkám, příušnicím a zarděnkám MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Úvod: Nárůst incidence spalniček začátkem roku 2019 vedl k provedení řady preventivních opatření zaměřených zejména na zdravotníky. Cílem práce bylo vyhodnotit jak séroprevalenci protilátek proti spalničkám mezi zaměstnanci velké nemocnice, tak míru sérokonverze na pilotním vzorku přeočkovaných s ročním odstupem. Metodika: 3 027 zaměstnanců Fakultní nemocnice Olomouc podstoupilo nabídnuté vyšetření hladiny specifického imunoglobulinu G s následnou možností přeočkování v případě nedostatečné hladiny. Zhruba po roce od přeočkování bylo u vzorku 52 zaměstnanců provedeno stejné vyšetření. Výsledky: V celém souboru testovaných zaměstnanců s průměrným věkem 41,8 ± 9,2 let byla séropozitivita prokázána u 54,0 % osob s jednoznačně vyšším zastoupením, a současně vyššími absolutními hodnotami protilátkových titrů, u zaměstnanců narozených před zahájením pravidelné vakcinace (rok 1969). Možnost přeočkování využilo 80,9 % séronegativních. Ze znovu otestovaných zaměstnanců pak sérokonverze nastala u 73,2 %. Relativní zvýšení titru protilátek po přeočkování korelovalo středně silně s věkem (r = 0,47, p < 0,05). Závěr: Podíl séronegativních zaměstnanců velké nemocnice dosáhl 46,0 % s vyšším zastoupením u mladších jedinců. Sérokonverze nastala u 73,2 % přeočkovaných zaměstnanců v opětovně vyšetřeném pilotním souboru. Byla zaznamenána statisticky významná korelace mezi relativním nárůstem titru protilátek a věkem.
Introduction: The increase in measles cases in early 2019 led to the implementation of several preventive measures focused mainly on health care providers. The study aimed to evaluate the seroprevalence of measles antibodies among employees of a large hospital and, a year apart, the rate of seroconversion in a pilot sample of the revaccinated subjects. Methods: In 3027 employees of the University Hospital Olomouc, specific immunoglobulin G levels were tested on a voluntary basis. Those with insufficient levels were offered a booster dose. About approximately one year after the booster dose, the same test was performed in a sample of 52 employees. Results: Of the tested subjects with a mean age of 41.8 ± 9.2 years, 54.0% were seropositive. A higher proportion of seropositivity as well as higher absolute values of antibody titers were noted in those born before routine vaccination was introduced in 1969. A total of 80.9% of the seronegative subjects opted for a booster dose. Seroconversion occurred in 73.2% of retested subjects. The relative increase of post-booster antibody titers was moderately correlated with age (r = 0.47, p < 0.05). Conclusion: The proportion of seronegative employees of a large hospital reached 46.0%, being higher in younger individuals. Seroconversion occurred in 73.2% of booster dose recipients included in a pilot sample for reanalysis. A statistically significant correlation was noted between the relative increase of antibody titers and age.
- MeSH
- lidé MeSH
- protilátky analýza MeSH
- sekundární imunizace MeSH
- séroepidemiologické studie MeSH
- sérokonverze MeSH
- spalničky * epidemiologie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
Lipophosphonoxins (LPPOs) are small modular synthetic antibacterial compounds that target the cytoplasmic membrane. First-generation LPPOs (LPPO I) exhibit an antimicrobial activity against Gram-positive bacteria; however they do not exhibit any activity against Gram-negatives. Second-generation LPPOs (LPPO II) also exhibit broadened activity against Gram-negatives. We investigated the reasons behind this different susceptibility of bacteria to the two generations of LPPOs using model membranes and the living model bacteria Bacillus subtilis and Escherichia coli. We show that both generations of LPPOs form oligomeric conductive pores and permeabilize the bacterial membrane of sensitive cells. LPPO activity is not affected by the value of the target membrane potential, and thus they are also active against persister cells. The insensitivity of Gram-negative bacteria to LPPO I is probably caused by the barrier function of the outer membrane with LPS. LPPO I is almost incapable of overcoming the outer membrane in living cells, and the presence of LPS in liposomes substantially reduces their activity. Further, the antimicrobial activity of LPPO is also influenced by the phospholipid composition of the target membrane. A higher proportion of phospholipids with neutral charge such as phosphatidylethanolamine or phosphatidylcholine reduces the LPPO permeabilizing potential.
- MeSH
- antibakteriální látky chemická syntéza farmakologie MeSH
- Bacillus subtilis chemie cytologie účinky léků MeSH
- Escherichia coli chemie cytologie účinky léků MeSH
- fosfatidylcholiny analýza metabolismus MeSH
- fosfatidylethanolaminy analýza metabolismus MeSH
- kationické antimikrobiální peptidy chemická syntéza farmakologie MeSH
- lipidové dvojvrstvy MeSH
- membránové potenciály účinky léků MeSH
- mikrobiální testy citlivosti MeSH
- permeabilita buněčné membrány MeSH
- vnější bakteriální membrána chemie účinky léků metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The ability of bacteria to develop resistance to antibiotics is threatening one of the pillars of modern medicine. It was recently understood that bacteria can develop resistance even to silver nanoparticles by starting to produce flagellin, a protein which induces their aggregation and deactivation. This study shows that silver covalently bound to cyanographene (GCN/Ag) kills silver-nanoparticle-resistant bacteria at concentrations 30 times lower than silver nanoparticles, a challenge which has been so far unmet. Tested also against multidrug resistant strains, the antibacterial activity of GCN/Ag is systematically found as potent as that of free ionic silver or 10 nm colloidal silver nanoparticles. Owing to the strong and multiple dative bonds between the nitrile groups of cyanographene and silver, as theory and experiments confirm, there is marginal silver ion leaching, even after six months of storage, and thus very high cytocompatibility to human cells. Molecular dynamics simulations suggest strong interaction of GCN/Ag with the bacterial membrane, and as corroborated by experiments, the antibacterial activity does not rely on the release of silver nanoparticles or ions. Endowed with these properties, GCN/Ag shows that rigid supports selectively and densely functionalized with potent silver-binding ligands, such as cyanographene, may open new avenues against microbial resistance.
Photodynamic inactivation (PDI) is a promising approach for the efficient killing of pathogenic microbes. In this study, the photodynamic effect of sulfonated polystyrene nanoparticles with encapsulated hydrophobic 5,10,15,20-tetraphenylporphyrin (TPP-NP) photosensitizers on Gram-positive (including multi-resistant) and Gram-negative bacterial strains was investigated. The cell viability was determined by the colony forming unit method. The results showed no dark cytotoxicity but high phototoxicity within the tested conditions. Gram-positive bacteria were more sensitive to TPP-NPs than Gram-negative bacteria. Atomic force microscopy was used to detect changes in the morphological properties of bacteria before and after the PDI treatment.
- MeSH
- Bacteria účinky léků účinky záření MeSH
- fotochemické procesy * MeSH
- fotochemoterapie metody MeSH
- mikroskopie atomárních sil MeSH
- nanočástice * chemie MeSH
- polystyreny * chemie MeSH
- porfyriny aplikace a dávkování chemie MeSH
- příprava léků * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
