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1.
Intern Emerg Med ; 16(8): 2129-2137, 2021 Nov.
Article En | MEDLINE | ID: mdl-33983474

Community-acquired pneumonia (CAP) is a common illness that can lead to mortality. ß-lactams are ineffective against atypical pathogen including Mycoplasma pneumoniae. We used molecular examinations to develop a decision tree to predict atypical pathogens with CAP and to examine the prevalence of macrolide resistance in Mycoplasma pneumoniae. We conducted a prospective observational study of patients aged ≥ 18 years who had fever and respiratory symptoms and were diagnosed with CAP in one of two community hospitals between December 2016 and October 2018. We assessed combinations of clinical variables that best predicted atypical pathogens with CAP by classification and regression tree (CART) analysis. Pneumonia was defined as respiratory symptoms and new infiltration recognized on chest X-ray or chest computed tomography. We analyzed 47 patients (21 females, 44.7%, mean age: 47.6 years). Atypical pathogens were detected in 15 patients (31.9%; 12 Mycoplasma pneumoniae, 3 Chlamydophila pneumoniae). Ten patients carried macrolide resistant Mycoplasma pneumoniae (macrolide resistant rate 83.3%). CART analysis suggested that factors associated with presence of atypical pathogens were absence of crackles, age < 45 years, and LD ≥ 183 U/L (sensitivity 86.7% [59.5, 98.3], specificity 96.9% [83.8, 99.9]). ur simple clinical decision rules can be used to identify primary care patients with CAP that are at risk for atypical pathogens. Further research is needed to validate its usefulness in various populations.Trial registration Clinical Trial (UMIN trial ID: UMIN000035346).


Pneumonia/etiology , Respiratory Tract Infections/complications , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Area Under Curve , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/pathogenicity , Community-Acquired Infections/complications , Community-Acquired Infections/epidemiology , Community-Acquired Infections/microbiology , Epidemiologic Studies , Female , Humans , Japan/epidemiology , Male , Middle Aged , Mycoplasma pneumoniae/drug effects , Mycoplasma pneumoniae/pathogenicity , Pneumonia/epidemiology , Pneumonia/microbiology , Polymerase Chain Reaction/methods , Prevalence , Prospective Studies , ROC Curve , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/microbiology
2.
Rev Esp Quimioter ; 34(2): 81-92, 2021 Apr.
Article Es | MEDLINE | ID: mdl-33749214

From a microbiological point of view, both empirical and targeted antimicrobial treatment in respiratory infection is based on the sensitivity profile of isolated microorganisms and the possible resistance mechanisms that they may present. The latter may vary in different geographic areas according to prescription profiles and vaccination programs. Beta-lactam antibiotics, fluoroquinolones, and macrolides are the most commonly used antimicrobials during the exacerbations of chronic obstructive pulmonary disease and community-acquired pneumonia. In their prescription, different aspects such as intrinsic activity, bactericidal effect or their ability to prevent the development of resistance must be taken into account. The latter is related to the PK/PD parameters, the mutant prevention concentration and the so-called selection window. More recently, the potential ecological impact has grown in importance, not only on the intestinal microbiota, but also on the respiratory one. Maintaining the state of eubiosis requires the use of antimicrobials with a low profile of action on anaerobic bacteria. With their use, the resilience of the bacterial populations belonging to the microbiota, the state of resistance of colonization and the collateral damage related to the emergence of resistance to the antimicrobials in pathogens causing the infections and in the bacterial populations integrating the microbiota.


Anti-Bacterial Agents/pharmacology , COVID-19/epidemiology , Drug Resistance, Bacterial , Pulmonary Disease, Chronic Obstructive/drug therapy , Respiratory Tract Infections/drug therapy , Administration, Oral , Anti-Bacterial Agents/administration & dosage , Chlamydophila pneumoniae/drug effects , Community-Acquired Infections/drug therapy , Community-Acquired Infections/microbiology , Disease Progression , Gastrointestinal Microbiome/drug effects , Haemophilus influenzae/drug effects , Humans , Microbial Sensitivity Tests , Moraxella catarrhalis/drug effects , Mycoplasma pneumoniae/drug effects , Pseudomonas aeruginosa/drug effects , Pulmonary Disease, Chronic Obstructive/microbiology , Respiratory Tract Infections/microbiology , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects
3.
PLoS One ; 15(6): e0234413, 2020.
Article En | MEDLINE | ID: mdl-32511255

BACKGROUND: Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory infection. There may exist an association between C. pneumoniae, asthma, and production of immunoglobulin (Ig) E responses in vitro. Interleukin (IL-4) is required for IgE production. OBJECTIVE: We previously demonstrated that doxycycline suppresses C. pneumoniae-induced production of IgE and IL-4 responses in peripheral blood mononuclear cells (PBMC) from asthmatic subjects. Whereas macrolides have anti-chlamydial activity, their effect on in vitro anti-inflammatory (IgE) and IL-4 responses to C. pneumoniae have not been studied. METHODS: PBMC from IgE- adult atopic subjects (N = 5) were infected +/- C. pneumoniae BAL69, +/- azithromycin (0.1, 1.0 ug/mL) for 10 days. IL-4 and IgE levels were determined in supernatants by ELISA. IL-4 and IgE were detected in supernatants of PBMC (day 10). RESULTS: When azithromycin (0.1, 1.0 ug/ml) was added, IL-4 levels decreased. At low dose, IgE levels increased and at high dose, IgE levels decreased. When PBMC were infected with C. pneumoniae, both IL-4 and IgE levels decreased. Addition of azithromycin (0.1, 1.0 ug/mL) decreased IL-4 levels and had no effect on IgE levels. CONCLUSIONS: These findings indicate that azithromycin decreases IL-4 responses but has a bimodal effect on IgE responses in PBMC from atopic patients in vitro.


Azithromycin/pharmacology , Chlamydophila pneumoniae/immunology , Immunoglobulin E/biosynthesis , Interleukin-4/biosynthesis , Aged , Anti-Bacterial Agents/pharmacology , Asthma/complications , Asthma/drug therapy , Asthma/immunology , Chlamydophila Infections/complications , Chlamydophila Infections/drug therapy , Chlamydophila Infections/immunology , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/pathogenicity , Female , Humans , Hypersensitivity, Immediate/complications , Hypersensitivity, Immediate/immunology , Hypersensitivity, Immediate/microbiology , Immunoglobulin E/blood , In Vitro Techniques , Interleukin-4/blood , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/microbiology , Male , Middle Aged , Respiratory Tract Infections/complications , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/immunology , Young Adult
4.
Infect Immun ; 88(4)2020 03 23.
Article En | MEDLINE | ID: mdl-31964747

Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections, and Chlamydia pneumoniae causes community-acquired respiratory infections. In vivo, the host immune system will release gamma interferon (IFN-γ) to combat infection. IFN-γ activates human cells to produce the tryptophan (Trp)-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). Consequently, there is a reduction in cytosolic Trp in IFN-γ-activated host cells. In evolving to obligate intracellular dependence, Chlamydia has significantly reduced its genome size and content, as it relies on the host cell for various nutrients. Importantly, C. trachomatis and C. pneumoniae are Trp auxotrophs and are starved for this essential nutrient when the human host cell is exposed to IFN-γ. To survive this, chlamydiae enter an alternative developmental state referred to as persistence. Chlamydial persistence is characterized by a halt in the division cycle, aberrant morphology, and, in the case of IFN-γ-induced persistence, Trp codon-dependent changes in transcription. We hypothesize that these changes in transcription are dependent on the particular amino acid starvation state. To investigate the chlamydial response mechanisms acting when other amino acids become limiting, we tested the efficacy of prokaryote-specific tRNA synthetase inhibitors, indolmycin and AN3365, to mimic starvation of Trp and leucine, respectively. We show that these drugs block chlamydial growth and induce changes in morphology and transcription consistent with persistence. Importantly, growth inhibition was reversed when the compounds were removed from the medium. With these data, we find that indolmycin and AN3365 are valid tools that can be used to mimic the persistent state independently of IFN-γ.


Adaptation, Physiological , Amino Acyl-tRNA Synthetases/antagonists & inhibitors , Chlamydia Infections/microbiology , Chlamydia trachomatis/growth & development , Chlamydophila pneumoniae/growth & development , Gene Expression Regulation, Bacterial , Tryptophan/metabolism , Cell Line , Chlamydia trachomatis/cytology , Chlamydia trachomatis/drug effects , Chlamydia trachomatis/enzymology , Chlamydophila pneumoniae/cytology , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/enzymology , Enzyme Inhibitors/metabolism , Host-Pathogen Interactions , Humans , Indoles/metabolism , Leucine/metabolism , Models, Biological , Transcription, Genetic
5.
Molecules ; 25(2)2020 Jan 11.
Article En | MEDLINE | ID: mdl-31940776

Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. The virulence of an intracellular human pathogen C. pneumoniae is tightly linked to its propensity for persistence and means for its chemosensitization are urgently needed. In the current work, persistence of C. pneumoniae clinical isolate CV6 was studied in THP-1 macrophages using quantitative PCR and quantitative culture. A dibenzocyclooctadiene lignan schisandrin reverted C. pneumoniae persistence and promoted productive infection. The concomitant administration of schisandrin and azithromycin resulted in significantly improved bacterial eradication compared to sole azithromycin treatment. In addition, the closely related lignan schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection from the macrophages. The observed chemosensitization of C. pneumoniae was associated with the suppression of cellular glutathione pools by the lignans, implying to a previously unknown aspect of chlamydia-host interactions. These data indicate that schisandrin lignans induce a phenotypic switch in C. pneumoniae, promoting the productive and antibiotic-susceptible phenotype instead of persistence. By this means, these medicinal plant -derived compounds show potential as adjuvant therapies for intracellular bacteria resuscitation.


Biological Assay/methods , Chlamydophila pneumoniae/physiology , Cyclooctanes/pharmacology , Lignans/pharmacology , Macrophages/microbiology , Azithromycin/administration & dosage , Azithromycin/pharmacology , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/growth & development , Cyclooctanes/administration & dosage , Cyclooctanes/chemistry , Glutathione/metabolism , Humans , Kinetics , Lignans/administration & dosage , Lignans/chemistry , Macrophages/drug effects , Oxidation-Reduction , Phenotype , Polycyclic Compounds/administration & dosage , Polycyclic Compounds/chemistry , Polycyclic Compounds/pharmacology , Reactive Oxygen Species/metabolism , THP-1 Cells
6.
Med Chem ; 16(3): 413-421, 2020.
Article En | MEDLINE | ID: mdl-31284867

BACKGROUND: In the past century, many phenazines were isolated from the marine microorganism, and some of these phenazines possessed potent antibacterial activities. We found that a few of the synthesized 4-substituted phenazines could block the infectivity of chlamydiae without host cell toxicity. OBJECTIVE: The aim of this study was to design and synthesize two series of novel 3-substituted phenazines to find novel antichlamydial agents. METHODS: The 3-substituted phenazines were synthesized via Buchwald-Hartwig cross coupling reaction and Suzuki reaction from 3-bromo-1-methoxyphenazine. The antichlamydial activity of these synthesized compounds was evaluated by determining their effect on the yield of infectious progeny EBs. Cytotoxicity of these compounds on host cells was assessed by the treatment of uninfected HeLa cells using WST-1 method. RESULTS: Most of the 3-substituted phenazines possessed potent antichlamydial activity with IC50 values from 0.15 to 12.08 µM against Chlamydia trachomatis L2, C. muridarum MoPn and C. pneumoniae AR39. Among them, 7d and 9a exhibited better antichlamydial activity with IC50 values from 0.20 to 1.01 µM while they have no apparent cytotoxicity to host cells. Biological assay disclosed that both 7d and 9a inhibited chlamydial infection by reducing elementary body infectivity and disturbing chlamydial growth during the whole chlamydial developmental cycle. CONCLUSION: Our findings suggested that 3-substituted phenazine derivatives might be a promising class of therapeutic agents for chlamydial infections. More effective phenazines with low toxicity could be acquired through further chemical modification on C-3 position rather than C-4 position of phenazine.


Anti-Bacterial Agents/pharmacology , Phenazines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Chlamydia trachomatis/drug effects , Chlamydophila pneumoniae/drug effects , Drug Design , HeLa Cells , Humans , Microbial Sensitivity Tests , Phenazines/chemical synthesis , Phenazines/toxicity
8.
Article En | MEDLINE | ID: mdl-31249813

Chlamydia trachomatis infections are the most prevalent sexually transmitted infections with potentially debilitating sequelae, such as infertility. Mouse models are generally used for vaccine development, to study the immune response and histopathology associated with Chlamydia infection. An important question regarding murine models is the in vivo identification of murine host genes responsible for the elimination of the murine and human Chlamydia strains. RNA sequencing of the Chlamydia muridarum infected BALB/c lung transcriptome revealed that several genes with direct antichlamydial functions were induced at the tissue level, including the already described and novel members of the murine interferon-inducible GTPase family, the CXCL chemokines CXCL9, CXCL11, immunoresponsive gene 1, nitric oxide synthase-2 (iNOS), and lipocalin-2. Indoleamine 2,3-dioxygenase 1-2 (IDO1-2) previously described potent antichlamydial host enzymes were also highly expressed in the infected murine lungs. This finding was novel, since IDO was considered as a unique human antichlamydial defense gene. Besides a lower level of epithelial cell positivity, immunohistochemistry showed that IDO1-2 proteins were expressed prominently in macrophages. Detection of the tryptophan degradation product kynurenine and the impact of IDO inhibition on Chlamydia muridarum growth proved that the IDO1-2 proteins were functionally active. IDO1-2 activity also increased in Chlamydia muridarum infected C57BL/6 lung tissues, indicating that this phenomenon is not mouse strain specific. Our study shows that the murine antichlamydial response includes a variety of highly up-regulated defense genes in vivo. Among these genes the antichlamydial effectors IDO1-2 were identified. The potential impact of murine IDO1-2 expression on Chlamydia propagation needs further investigation.


Chlamydia Infections/metabolism , Chlamydia muridarum/drug effects , Chlamydia muridarum/metabolism , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/pharmacology , Lung/metabolism , Animals , Chemokine CXCL11/genetics , Chemokine CXCL11/metabolism , Chemokine CXCL9/genetics , Chemokine CXCL9/metabolism , Chemokines/genetics , Chemokines/metabolism , Chlamydia Infections/genetics , Chlamydia Infections/microbiology , Chlamydia Infections/pathology , Disease Models, Animal , Enzyme Inhibitors/metabolism , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Gene Expression , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Kynurenine , Lipocalin-2/genetics , Lipocalin-2/metabolism , Lung/pathology , Macrophages/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , RNA, Messenger/metabolism , Transcriptome , Tryptophan/analogs & derivatives , Tryptophan/antagonists & inhibitors , Tryptophan/metabolism
9.
APMIS ; 127(3): 131-138, 2019 Mar.
Article En | MEDLINE | ID: mdl-30746791

Obligate intracellular bacterium Chlamydia pneumoniae causes respiratory tract infections such as community-acquired pneumonia. During infection, C. pneumoniae induces inflammatory responses in host cells and the oxygen concentration at the infection sites subsequently decreases. Because hypoxic conditions influence further inflammatory responses and reduced antibacterial effects, this may exacerbate the C. pneumoniae infection. Here, we show inflammatory responses and drug sensitivity in C. pneumoniae-infected cells under hypoxic conditions. First, we confirmed the enhanced growth of C. pneumoniae under hypoxia, which indicates that the hypoxic condition we used could adequately reproduce past reports. We then demonstrated a significant increase in production of the pro-inflammatory cytokine Interleukin 8 (IL-8) in C. pneumoniae-infected cells under hypoxic conditions. Furthermore, hypoxia decreased the antibacterial effects of azithromycin against C. pneumoniae compared with normoxic conditions. Together, our data suggest that inflammatory responses and drug sensitivity may have been underestimated in C. pneumoniae infection in previous studies. Thus, to accurately understand the Chlamydia infection, it may be necessary to perform in vitro experiments under hypoxic conditions.


Azithromycin/pharmacology , Cell Hypoxia/immunology , Chlamydophila Infections , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/physiology , Host-Pathogen Interactions , Interleukin-8/metabolism , Anti-Bacterial Agents/pharmacology , Cell Line , Chlamydophila Infections/immunology , Chlamydophila Infections/microbiology , Chlamydophila pneumoniae/growth & development , Drug Resistance, Bacterial/physiology , Humans , Microbial Sensitivity Tests
10.
Mil Med ; 184(7-8): e196-e199, 2019 07 01.
Article En | MEDLINE | ID: mdl-30690452

INTRODUCTION: Chlamydia pneumoniae (Cp) is a bacterium that causes pneumonia and other respiratory diseases. Fever may be present early but absent by time of presentation to clinic. Increases in X-ray-confirmed pneumonia (XCP) and laboratory-confirmed Cp infections were observed in new soldiers in training at Fort Leonard Wood (FLW), Missouri, early in 2014. These findings prompted a site assistance visit from the U.S. Army Public Health Command, Aberdeen Proving Ground, Maryland, with a review of available data and information to describe the outbreak, and inspections of barracks and training facilities and review of training practices to identify opportunities for interventions to reduce the risk of respiratory disease agent transmission. MATERIALS AND METHODS: The study population was trainee soldiers at FLW in 2013-2014. Data from two acute respiratory disease surveillance systems were studied. A local surveillance system operated by the FLW General Leonard Wood Army Community Hospital Preventive Medicine Department tracked weekly chest X-rays taken and the numbers positive for pneumonia. A Naval Health Research Center, San Diego, California, laboratory-based Febrile Respiratory Illness Surveillance Program collected clinical data and nasal, or nasal and pharyngeal swabs, for nucleic acid amplification testing from up to 15 trainees/week with fever and either cough or sore throat. Up to 4 of the 15 specimens could be from afebrile patients with XCP. Specimens were tested for a variety of agents. RESULTS: Monthly rates of XCP rose quickly in 2014 and peaked at 0.9/100 trainees in May. The percentage of the San Diego surveillance system specimens that were positive for Cp also increased quickly in 2014, peaking at 54% in May. During the first half of 2014, the San Diego program studied specimens from 141 ill trainees; 37% (52/141) were positive for Cp, making it the most common organism identified, followed by rhinoviruses (8%), influenza viruses (4%), Mycoplasma pneumoniae (2%), and adenoviruses (1%). The remaining specimens (48%) were negative for all respiratory pathogens. Only 12% (6/52) of Cp positive patients were febrile. Facilities inspections and review of training practices failed to identify variables that might be contributing to an increased risk of respiratory agent transmission. CONCLUSION: The XCP rate and the percentage of specimens positive for Cp increased in early 2014, peaking in May. Only 12% of trainees with laboratory-confirmed Cp were febrile. Historically, acute respiratory disease surveillance at military training centers focused on febrile diseases, particularly those caused by adenoviruses. With introduction of an adenovirus vaccine in late 2011, respiratory disease rates dropped with only sporadic occurrences of adenovirus-associated disease. In 2012, the San Diego surveillance program began providing data on multiple respiratory disease agents, in addition to adenoviruses and influenza viruses. Since then, Cp, rhinoviruses and Mycoplasma pneumoniae have frequently been detected in trainees with acute respiratory disease. Respiratory surveillance programs supporting Army training centers should be re-evaluated in this post-adenovirus vaccine era, to include assessment of the fever criterion for selecting patients for study, the value of chest X-ray surveillance and the value of rapidly providing laboratory results to inform provider decisions regarding antibiotic use.


Chlamydophila Infections/complications , Military Personnel/statistics & numerical data , Pneumonia/etiology , Chlamydophila Infections/epidemiology , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/pathogenicity , Disease Outbreaks , Female , Humans , Male , Missouri/epidemiology , Pneumonia/epidemiology , Population Surveillance/methods , Radiography/methods , Radiography/statistics & numerical data , Students/statistics & numerical data , Teaching/statistics & numerical data , Young Adult
11.
Article En | MEDLINE | ID: mdl-30509942

The in vitro activities of omadacycline, azithromycin, doxycycline, moxifloxacin, and levofloxacin were tested against 15 isolates of Chlamydia pneumoniae The minimum inhibitory concentration at which 90% of the isolates of C. pneumoniae were inhibited by omadacycline was 0.25 µg/ml (range, 0.03 to 0.5 µg/ml).


Anti-Bacterial Agents/pharmacology , Chlamydophila pneumoniae/drug effects , Tetracyclines/pharmacology , Azithromycin/pharmacology , Cell Line , Chlamydial Pneumonia/drug therapy , Chlamydial Pneumonia/microbiology , Chlamydophila pneumoniae/isolation & purification , Doxycycline/pharmacology , Humans , Levofloxacin/pharmacology , Microbial Sensitivity Tests , Moxifloxacin/pharmacology
12.
J Med Microbiol ; 67(9): 1410-1415, 2018 Sep.
Article En | MEDLINE | ID: mdl-30074473

PURPOSE: The antimicrobial activity of N-chlorotaurine (NCT), an endogenous long-lived oxidant applied topically, was tested against Chlamydiae in vitro. METHODOLOGY: Elementary bodies of Chlamydia pneumoniae strain CV-6 and Chlamydia trachomatis serovars A and D were incubated in 0.01, 0.1 and 1 % (w/v) NCT solution at pH 7.1 and 37 °C. After different incubation times, aliquots were removed and grown in cell culture. The number of inclusion forming units was quantified by immunofluorescence and real-time qPCR.Results/Key findings.Chlamydia pneumoniae and Chlamydia trachomatis were inactivated by 1 and 0.1 % NCT within 1 min. Moreover, 0.025-0.1 % NCT significantly reduced the number of intracellularly growing C. pneumoniae within 30 min. CONCLUSIONS: This is the first study demonstrating the antimicrobial activity of NCT against Chlamydiae. Clinical implications of these findings have to be investigated in further trials.


Anti-Infective Agents, Local/pharmacology , Chlamydia trachomatis/drug effects , Chlamydophila Infections/microbiology , Chlamydophila pneumoniae/drug effects , Taurine/analogs & derivatives , Chlamydia Infections , Chlamydia trachomatis/growth & development , Chlamydophila pneumoniae/genetics , Chlamydophila pneumoniae/growth & development , Chlamydophila pneumoniae/metabolism , Humans , Taurine/pharmacology
13.
J Infect Chemother ; 24(2): 130-137, 2018 Feb.
Article En | MEDLINE | ID: mdl-29132924

Chlamydia trachomatis is the leading cause of sexually transmitted infections worldwide. Capsaicin, a component of chili pepper, which can stimulate actin remodeling via capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) and anti-inflammatory effects via PPARγ (peroxisome proliferator-activated receptor-γ) and LXRα (liver X receptor α), is a potential candidate to control chlamydial growth in host cells. We examined whether capsaicin could inhibit C. trachomatis growth in immortal human epithelial HeLa cells. Inclusion forming unit and quantitative PCR assays showed that capsaicin significantly inhibited bacterial growth in cells in a dose-dependent manner, even in the presence of cycloheximide, a eukaryotic protein synthesis inhibitor. Confocal microscopic and transmission electron microscopic observations revealed an obvious decrease in bacterial numbers to inclusions bodies formed in the cells. Although capsaicin can stimulate the apoptosis of cells, no increase in cleaved PARP (poly (ADP-ribose) polymerase), an apoptotic indicator, was observed at a working concentration. All of the drugs tested (capsazepine, a TRPV1 antagonist; 5CPPSS-50, an LXRα inhibitor; and T0070907, a PPARγ inhibitor) had no effect on chlamydial inhibition in the presence of capsaicin. In addition, we also confirmed that capsaicin inhibited Chlamydia pneumoniae growth, indicating a phenomena not specific to C. trachomatis. Thus, we conclude that capsaicin can block chlamydial growth without the requirement of host cell protein synthesis, but by another, yet to be defined, mechanism.


Capsaicin/pharmacology , Chlamydia trachomatis/drug effects , Chlamydophila pneumoniae/drug effects , Apoptosis/drug effects , Cell Proliferation/drug effects , Chlamydia trachomatis/growth & development , Chlamydophila pneumoniae/growth & development , Cycloheximide/pharmacology , Dose-Response Relationship, Drug , HeLa Cells , Humans , Inclusion Bodies/drug effects , Liver X Receptors/antagonists & inhibitors , PPAR gamma/antagonists & inhibitors , Protein Synthesis Inhibitors/pharmacology , TRPV Cation Channels/antagonists & inhibitors
14.
Biomed Res Int ; 2017: 3120138, 2017.
Article En | MEDLINE | ID: mdl-29057257

OBJECTIVE: To understand the prevalence and distribution of Chlamydia pneumoniae (CP) and Mycoplasma pneumoniae (MP) in the population and to provide a basis for the prevention and treatment of respiratory tract infection. METHODS: This study included a total of 4500 healthy subjects who were given physical examination in Shenzhen People's Hospital from January to December in 2016. Venous blood was drawn from people to detect the MP- and CP-specific IgG and IgM in the serum using chemiluminescence immunoassay (CLIA). The relationship of MP and CP infections with patient age, seasons, and percentage of infections was analyzed. CONCLUSION: CP and MP cause high rate of asymptomatic infection, which may be associated with the high incidence of CP and MP infection, especially in children and the elderly population. Therefore, the implementation of effective and practical prevention measures has become an urgent need. MP culture and drug sensitivity test should be performed as early as possible in patients with manifested MP infections in order to ensure timely and proper treatment and to reduce the emergence of drug-resistant strains.


Chlamydophila Infections/blood , Chlamydophila pneumoniae/isolation & purification , Mycoplasma pneumoniae/isolation & purification , Pneumonia, Mycoplasma/blood , Adolescent , Adult , Aged , Antibodies, Bacterial/blood , Antibodies, Bacterial/isolation & purification , Child , Child, Preschool , China/epidemiology , Chlamydophila Infections/drug therapy , Chlamydophila Infections/microbiology , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/pathogenicity , Drug Resistance, Bacterial/genetics , Female , Humans , Male , Middle Aged , Mycoplasma pneumoniae/drug effects , Mycoplasma pneumoniae/pathogenicity , Pneumonia, Mycoplasma/drug therapy , Pneumonia, Mycoplasma/microbiology , Respiratory Tract Infections/blood , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiology , Serologic Tests
15.
J Nat Prod ; 80(10): 2602-2608, 2017 10 27.
Article En | MEDLINE | ID: mdl-29043803

The obligate intracellular pathogen Chlamydia pneumoniae remains a difficult target for antimicrobial therapy. Owing to the permeability barrier placed by bacterial and host vacuolar membranes, as well as the propensity of the bacterium for persistent infections, treatment failures are common. Despite the urgent need for new antichlamydial compounds, their discovery is challenged by the technically demanding assay procedures and lack of validated targets. An alternative strategy of using naturally occurring compounds and their derivatives against C. pneumoniae is presented. The strategy consists of the application of ligand-based virtual screening to a natural product library of 502 compounds with the ChemGPS-NP chemography tool followed by in vitro antichlamydial assays. The reference set used for the 2D similarity search was constructed of 19 known antichlamydial compounds of plant origin. Based on the similarity screen, 53 virtual hits were selected for in vitro testing. Six compounds (leads) were identified that cause ≥50% C. pneumoniae growth inhibition and showed no impact on host cell viability. The leads fall into completely new antichlamydial chemotypes, one of them being mycophenolic acid (IC50 value 0.3 µM). The outcome indicates that using this flipped, target-independent strategy is useful for facilitating the antimicrobial lead discovery against challenging microbes.


Anti-Bacterial Agents/pharmacology , Biological Products/pharmacology , Chlamydophila pneumoniae/drug effects , Anti-Bacterial Agents/chemistry , Azithromycin/pharmacology , Biological Products/chemistry , Cell Line , Cell Survival/drug effects , Drug Discovery , Humans , Ligands , Microbial Sensitivity Tests , Molecular Structure
16.
Bioorg Med Chem Lett ; 27(19): 4576-4577, 2017 10 01.
Article En | MEDLINE | ID: mdl-28867456

The antimicrobial activity of bitespiramycin (BT) against Chlamydia trachomatis (Ct), Chlamydia pneumoniae (Cp), Ureaplasma urealyticum (Uu), and Mycoplasma pneumoniae (Mp), was compared with those of azithromycin (AZM) and acetylspiramycin (AT-SP) in vitro. Furthermore, the anti-Mp activities of BT and AZM were evaluated in a hamster model. The activities of BT in vitro were similar to those of AZM but were more effective than those of AT-SP. BT effectively inhibited Mp infection at a dose of 200mg/kg in a hamster model.


Anti-Bacterial Agents/pharmacology , Chlamydia trachomatis/drug effects , Chlamydophila pneumoniae/drug effects , Mycoplasma pneumoniae/drug effects , Spiramycin/analogs & derivatives , Ureaplasma urealyticum/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Spiramycin/chemical synthesis , Spiramycin/chemistry , Spiramycin/pharmacology , Structure-Activity Relationship
17.
Article En | MEDLINE | ID: mdl-28696231

The nafithromycin concentrations in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin at 800 mg once daily for 3 days. The values of noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-h interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24, or 48 h after the third dose of nafithromycin. The mean ± standard deviation values of the plasma PK parameters after the first and third doses included maximum plasma concentrations (Cmax) of 1.02 ± 0.31 µg/ml and 1.39 ± 0.36 µg/ml, respectively; times to Cmax of 3.97 ± 1.30 h and 3.69 ± 1.28 h, respectively; clearances of 67.3 ± 21.3 liters/h and 52.4 ± 18.5 liters/h, respectively, and elimination half-lives of 7.7 ± 1.1 h and 9.1 ± 1.7 h, respectively. The values of the area under the plasma concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0-24) for nafithromycin based on the mean or median total plasma concentrations at BAL fluid sampling times were 16.2 µg · h/ml. For ELF, the respective AUC0-24 values based on the mean and median concentrations were 224.1 and 176.3 µg · h/ml, whereas for AM, the respective AUC0-24 values were 8,538 and 5,894 µg · h/ml. Penetration ratios based on ELF and total plasma AUC0-24 values based on the mean and median concentrations were 13.8 and 10.9, respectively, whereas the ratios of the AM to total plasma concentrations based on the mean and median concentrations were 527 and 364, respectively. The sustained ELF and AM concentrations for 48 h after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections. (This study has been registered at ClinicalTrials.gov under registration no. NCT02453529.).


Anti-Bacterial Agents/blood , Anti-Bacterial Agents/pharmacokinetics , Bronchoalveolar Lavage Fluid/chemistry , Ketolides/blood , Ketolides/pharmacokinetics , Lactones/pharmacology , Pneumonia, Bacterial/drug therapy , Adult , Anti-Bacterial Agents/adverse effects , Bronchoalveolar Lavage , Bronchoscopy , Chlamydophila pneumoniae/drug effects , Female , Haemophilus influenzae/drug effects , Healthy Volunteers , Humans , Ketolides/chemistry , Ketolides/pharmacology , Lactones/chemistry , Legionella pneumophila/drug effects , Macrophages, Alveolar/cytology , Male , Middle Aged , Moraxella catarrhalis/drug effects , Mycoplasma pneumoniae/drug effects , Pneumonia, Bacterial/microbiology , Pulmonary Alveoli/chemistry , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Young Adult
18.
Respir Res ; 18(1): 98, 2017 05 19.
Article En | MEDLINE | ID: mdl-28526018

Asthma is a chronic respiratory disease characterized by reversible airway obstruction and airway hyperresponsiveness to non-specific bronchoconstriction agonists as the primary underlying pathophysiology. The worldwide incidence of asthma has increased dramatically in the last 40 years. According to World Health Organization (WHO) estimates, over 300 million children and adults worldwide currently suffer from this incurable disease and 255,000 die from the disease each year. It is now well accepted that asthma is a heterogeneous syndrome and many clinical subtypes have been described. Viral infections such as respiratory syncytial virus (RSV) and human rhinovirus (hRV) have been implicated in asthma exacerbation in children because of their ability to cause severe airway inflammation and wheezing. Infections with atypical bacteria also appear to play a role in the induction and exacerbation of asthma in both children and adults. Recent studies confirm the existence of an infectious asthma etiology mediated by Chlamydia pneumoniae (CP) and possibly by other viral, bacterial and fungal microbes. It is also likely that early-life infections with microbes such as CP could lead to alterations in the lung microbiome that significantly affect asthma risk and treatment outcomes. These infectious microbes may exacerbate the symptoms of established chronic asthma and may even contribute to the initial development of the clinical onset of the disease. It is now becoming more widely accepted that patterns of airway inflammation differ based on the trigger responsible for asthma initiation and exacerbation. Therefore, a better understanding of asthma subtypes is now being explored more aggressively, not only to decipher pathophysiologic mechanisms but also to select treatment and guide prognoses. This review will explore infection-mediated asthma with special emphasis on the protean manifestations of CP lung infection, clinical characteristics of infection-mediated asthma, mechanisms involved and antibiotic treatment outcomes.


Asthma/drug therapy , Asthma/immunology , Chlamydophila Infections/drug therapy , Chlamydophila Infections/immunology , Chlamydophila pneumoniae/immunology , Macrolides/immunology , Anti-Bacterial Agents/therapeutic use , Asthma/epidemiology , Chlamydophila Infections/epidemiology , Chlamydophila pneumoniae/drug effects , Chlamydophila pneumoniae/isolation & purification , Humans , Macrolides/isolation & purification , Pneumonia, Bacterial/drug therapy , Pneumonia, Bacterial/epidemiology , Pneumonia, Bacterial/immunology , Treatment Outcome
19.
Vestn Otorinolaringol ; 81(4): 60-63, 2016.
Article Ru | MEDLINE | ID: mdl-27500582

The present study included 201 adult patients presenting with exacerbation of chronic maxillary sinusitis. The presence of Chlamydia trachomatis and Chl. pneumoniae was verified by the direct immunofluorescencetechnique and polymerase chain reaction. The study material consisted of swipes und swabs from the mucous membrane of the middle nasal passage. The information from the patients was collected with the use of a questionnaire specially elaborated for the purpose of this study. The correlation relationships were established by means of gamma-statistics. The method is based on the calculation of the integral index characterizing the risk of development of chlamydial infection using the scoring scale for the evaluation of the clinical and anamnestic characteristics of the patients. The assessment of the risk of chlamydial colonization by the anamnestic method makes it possible to enhance the effectiveness of clinical diagnostics of chlamydial infection and thereby provides a basis for the prescription of the adequate anti-chlamydial treatment facilitating reduction of the frequency of complications and preventing dissemination of the causative factor of the disease. Moreover, this approach creates the conditions for the targeted selection of the patients to be referred to the laboratory verification of Chlamydia. Highoperating performance and effectiveness characteristics of the clinic-anamnestic diagnostics make it a method of choice for the wide application in the clinical practice.


Anti-Bacterial Agents/therapeutic use , Chlamydia Infections , Chlamydia trachomatis , Chlamydophila pneumoniae , Maxillary Sinusitis , Adult , Bacteriological Techniques/methods , Chlamydia Infections/complications , Chlamydia Infections/diagnosis , Chlamydia Infections/drug therapy , Chlamydia Infections/microbiology , Chlamydia trachomatis/drug effects , Chlamydia trachomatis/isolation & purification , Chlamydophila pneumoniae/drug effects , Female , Humans , Male , Maxillary Sinusitis/diagnosis , Maxillary Sinusitis/drug therapy , Maxillary Sinusitis/microbiology , Maxillary Sinusitis/physiopathology , Microbial Sensitivity Tests/methods , Middle Aged , Risk Assessment , Secondary Prevention , Treatment Outcome
20.
Nat Prod Commun ; 11(11): 1725-1728, 2016 Nov.
Article En | MEDLINE | ID: mdl-30475517

The impact of solvent extracts from the distillation water (flavoring extracts) isolated from mint flavored candies on the infectivity of the intracellular bacterium Chlamydia pneumoniae was evaluated by an in vitro model of epithelial cell infections., The mint flavoring extracts were isolated from the candies by simultaneous hydrodistillation and their chemical composition, established by GC-MS, demonstrated menthol and limonene as the most abundant components. Results obtained by treating C. pneumoniae elementary bodies (EBs) with the flavoring extracts or pure reference compounds showed a significant decrease in EB infectivity, achieved with most of the extracts. This antichlamydial activity could be related to the relatively high menthol content of the extracts. Overall, the obtained data indicates that the flavorings present in the candies are able to target the metabolically quiet, non-replicating form of the bacterium and to suppress the spread of this respiratory pathogen from one cell to another.


Candy/analysis , Chlamydophila pneumoniae/drug effects , Flavoring Agents/pharmacology , Mentha/chemistry , Cell Line , Cell Survival/drug effects , Epithelial Cells/drug effects , Flavoring Agents/chemistry , Humans
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