Antimycobacterial pyridine carboxamides: From design to in vivo activity.

Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed.

Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid.

Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens.

Antibiotic-Loaded Amphiphilic Chitosan Nanoparticles Target Macrophages and Kill an Intracellular Pathogen.

In this work, levofloxacin (LVX), a third-generation fluoroquinolone antibiotic, is encapsulated within amphiphilic polymeric nanoparticles of a chitosan-g-poly(methyl methacrylate) produced by self-assembly and physically stabilized by ionotropic crosslinking with sodium tripolyphosphate. Non-crosslinked nanoparticles display a size of 29 nm and a zeta-potential of +36 mV, while the crosslinked counterparts display 45 nm and +24 mV, respectively. The cell compatibility, uptake, and intracellular trafficking are characterized in the murine alveolar macrophage cell line MH-S and the human bronchial epithelial cell line BEAS-2B in vitro.

Acute Pneumonia Caused by Clinically Isolated Sg 1, ST 62: Host Responses and Pathologies in Mice.

Legionnaires' disease is a severe form of lung infection caused by bacteria belonging to the genus . The disease severity depends on both host immunity and virulence. The objective of this study was to describe the pathological spectrum of acute pneumonia caused by a virulent clinical isolate of serogroup 1, sequence type 62.

Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice.

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-19. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-19. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2).

Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease.

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19) . We developed a bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C135 . CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor.

Development and Inter-Laboratory Validation of Diagnostics Panel for Detection of Biothreat Bacteria Based on MOL-PCR Assay.

Early detection of biohazardous bacteria that can be misused as biological weapons is one of the most important measures to prevent the spread and outbreak of biological warfare. For this reason, many instrument platforms need to be introduced into operation in the field of biological warfare detection. Therefore the purpose of this study is to establish a new detection panel for biothreat bacteria (, , and spp.

Antitubercular nanocarrier monotherapy: Study of In Vivo efficacy and pharmacokinetics for rifampicin.

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles.

Development of 3,5-Dinitrophenyl-Containing 1,2,4-Triazoles and Their Trifluoromethyl Analogues as Highly Efficient Antitubercular Agents Inhibiting Decaprenylphosphoryl-β-d-ribofuranose 2'-Oxidase.

We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against HRv and against seven clinically isolated multidrug-resistant strains of were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues.

Rifampicin Nanoformulation Enhances Treatment of Tuberculosis in Zebrafish.

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of alveolar macrophages. These cells avidly take up nanoparticles, even without the use of specific targeting ligands, making the use of nanotherapeutics ideal for the treatment of such infections. Methoxy poly(ethylene oxide)- block-poly(ε-caprolactone) nanoparticles of several different polymer blocks' molecular weights and sizes (20-110 nm) were developed and critically compared as carriers for rifampicin, a cornerstone in tuberculosis therapy.

Development of water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents.

In this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against Mycobacterium tuberculosis CNCTC My 331/88 (HRv), comparable to those of the first-line drugs isoniazid and rifampicin.

S-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents.

Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.

Tacrine alters antibodies level in Francisella tularensis-infected mice.

Objectives: Tacrine is an inhibitor of acetylcholinestrase (AChE) formerly used to treat cognitive impairment of Alzheimer disease. In previous works, we have shown that inhibitors of AChE can modulate innate immunity responses. In the present study we focused on modulation of adaptive immunity represented by production of antibodies.

Organs of BALB/c mice can be injured in course of tularemia.

Background: Francisella tularensis is a biological agent exploitable for bioterrorism and biological warfare purposes due to serious pathogenic progression and easy dissemination. Despite intensive research in the past, some adverse consequences remain unclear. One consequence of this pathogen is oxidative stress.

Our experience using real-time PCR for the detection of the gene that encodes the superficial lipoprotein LipL32 of the pathogenic leptospires to confirm the acute form of human leptospirosis.

Aims: To examine biological materials (blood, urine, cerebrospinal fluid) of patients with suspected leptospirosis using real-time PCR for detecting the gene that codes the superficial LipL32 lipoprotein, and to evaluate the contribution of the real-time PCR method for the laboratory diagnosis of the acute form of leptospirosis.

Material And Methods: During the monitored period of April 2010 - December 2011, a total of 340 biological materials samples were examined (177x blood plasma, 88x urine, 68x, cerebrospinal fluid, 6x bronchoalveolar lavage and 1x sputum) from 216 patients with suspected leptospirosis using real-time PCR LipL32 gene detection.

Results: From the mentioned 216 patients suspected of leptospirosis, 8 patients were evaluated as being PCR LipL32 positive, from which 14 positive biological materials originated (9 x urine, 4x blood and 1x liquor).

Galantamine effect on tularemia pathogenesis in a BALB/c mouse model.

Background: Galantamine is a drug used for the treatment of Alzheimer's disease and some other cognitive disorders. It is an inhibitor of acetylcholinesterase; however, interaction with nicotinic acetylcholine receptors has also been reported. Owing to the significant role of cholinergic anti-inflammatory pathways in neuro-immunomodulation, we decided to examine the effect of galantamine on tularemia-infected BALB/c mice.

Acetylcholine and an acetylcholinesterase inhibitor neostigmine can aggravate tularemia progress in BALB/c mice.

The present experiment was aimed at assessing the application of neostigmine, an acetylcholinesterase (AChE) pseudo-irreversible inhibitor with poor penetration through the hematoencephalitic barrier, and the neurotransmitter acetylcholine (ACh). The experiment was done to evaluate their ability to modulate an infectious disease: tularemia. Mice infected with Franciselle tularensis and exposed to either ACh or neostigmine had a higher mortality and spleen bacterial burden when compared to infected mice exposed to saline solution only.

Tularemia progression accompanied with oxidative stress and antioxidant alteration in spleen and liver of BALB/c mice.

Francisella tularensis is the causative agent of tularemia. It is an intracellular pathogen with the ability to survive within phagosomes and induce pyroptotic cell death. In this study, we attempted to prove whether oxidative imbalance plays a significant role in tularemia pathogenesis.

[Comparison of results of two serological methods for diagnosing leptospirosis - microagglutination test and ELISA].

Background: The aim of this study was to evaluate diagnostic sensitivity and specificity of the SERION ELISA classic IgM and SERION ELISA classic IgG kits and to confirm the results by the microagglutination test (MAT).

Material And Methods: A total of 45 blood serum samples from 45 patients, 30 from males and 15 from females (mean age 44.24 ± 15.

[Incidence of leptospirosis in Pardubice and Hradec Králové region and a part of Vysočina region in the years 2002-2009].

Background: The aim of this study was to evaluate the incidence of leptospirosis in Pardubice and Hradec Králové regions and a part of Vysočina region in 2002-2009. A group of patients was statistically analyzed and the incidence rates of leptospirosis in individual months and years were calculated.

Material And Methods: A group of 4,813 patients with suspected leptospirosis from Pardubice and Hradec Králové regions and a part of Vysočina region were examinated in our centre in 2002-2009.

[Microbiological and clinical aspects of tularaemia].

Francisella tularensis belongs to the most important biological agents potentially applicable in biological warfare and bioterrorism. High virulence, easy and rapid spread among individual vectors, stability of the cells in aerosol and good penetration into the lungs make F. tularensis one of the most important biological warfare agents in both human and veterinary medicine.

Assessment of low-molecular-weight antioxidants in Francisella tularensis infected hosts: comparison of two rodents with different susceptibility to tularemia.

Objectives: Bacterium Francisella tularensis is the causative agent of tularemia disease. It is a zoonosis accompanied with high mortality when untreated. Small rodents and hares, in particular, are natural reservoirs of tularemia.

Label-free piezoelectric immunosensor for rapid assay of Escherichia coli.

A piezoelectric sensor with immobilized polyclonal antibody was developed as a label-free assay for the model bacterium, Escherichia coli. The polyclonal antibody was prepared from mice BALB/c and covalently immobilized on the sensing gold electrode of the piezoelectric quartz crystal. The biosensor was able to detect E.