scholarly journals Comparison of the in Vivo Activities of Garenoxacin and Levofloxacin in a Murine Model of Pneumonia by Mixed-Infection with Streptococcus pneumoniae and Parvimonas micra

2019 ◽  
Vol 72 (6) ◽  
pp. 407-412
Author(s):  
Hideo Kato ◽  
Mao Hagihara ◽  
Yuki Yokoyama ◽  
Hiroyuki Suematsu ◽  
Nobuhiro Asai ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mixed Infection ◽  
Murine Model ◽  
Parvimonas Micra

scholarly journals Experimental Evolution In Vivo To Identify Selective Pressures during Pneumococcal Colonization

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Vaughn S. Cooper ◽  
Erin Honsa ◽  
Hannah Rowe ◽  
Christopher Deitrick ◽  
Amy R. Iverson ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Murine Model ◽  
Experimental Evolution ◽  
Nasal Colonization ◽  
Content Type ◽  
Selective Pressures ◽  
Specific Tissue ◽  
Tissue Tropisms ◽  
Insight Into

ABSTRACT Experimental evolution is a powerful technique to understand how populations evolve from selective pressures imparted by the surrounding environment. With the advancement of whole-population genomic sequencing, it is possible to identify and track multiple contending genotypes associated with adaptations to specific selective pressures. This approach has been used repeatedly with model species in vitro, but only rarely in vivo. Herein we report results of replicate experimentally evolved populations of Streptococcus pneumoniae propagated by repeated murine nasal colonization with the aim of identifying gene products under strong selection as well as the population genetic dynamics of infection cycles. Frameshift mutations in one gene, dltB, responsible for incorporation of d-alanine into teichoic acids on the bacterial surface, evolved repeatedly and swept to high frequency. Targeted deletions of dltB produced a fitness advantage during initial nasal colonization coupled with a corresponding fitness disadvantage in the lungs during pulmonary infection. The underlying mechanism behind the fitness trade-off between these two niches was found to be enhanced adherence to respiratory cells balanced by increased sensitivity to host-derived antimicrobial peptides, a finding recapitulated in the murine model. Additional mutations that are predicted to affect trace metal transport, central metabolism, and regulation of biofilm production and competence were also selected. These data indicate that experimental evolution can be applied to murine models of pathogenesis to gain insight into organism-specific tissue tropisms. IMPORTANCE Evolution is a powerful force that can be experimentally harnessed to gain insight into how populations evolve in response to selective pressures. Herein we tested the applicability of experimental evolutionary approaches to gain insight into how the major human pathogen Streptococcus pneumoniae responds to repeated colonization events using a murine model. These studies revealed the population dynamics of repeated colonization events and demonstrated that in vivo experimental evolution resulted in highly reproducible trajectories that reflect the environmental niche encountered during nasal colonization. Mutations impacting the surface charge of the bacteria were repeatedly selected during colonization and provided a fitness benefit in this niche that was counterbalanced by a corresponding fitness defect during lung infection. These data indicate that experimental evolution can be applied to models of pathogenesis to gain insight into organism-specific tissue tropisms.

scholarly journals Experimental Evolution in vivo to Identify Selective Pressures During Pneumococcal Colonization

2020 ◽  
Author(s):  
Vaughn S. Cooper ◽  
Erin Honsa ◽  
Hannah Rowe ◽  
Christopher Deitrick ◽  
Amy R. Iverson ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Murine Model ◽  
Experimental Evolution ◽  
Nasal Colonization ◽  
Environmental Niche ◽  
Selective Pressures ◽  
Specific Tissue ◽  
Tissue Tropisms ◽  
Insight Into

AbstractExperimental evolution is a powerful technique to understand how populations evolve from selective pressures imparted by the surrounding environment. With the advancement of whole-population genomic sequencing it is possible to identify and track multiple contending genotypes associated with adaptations to specific selective pressures. This approach has been used repeatedly with model species in vitro, but only rarely in vivo. Herein we report results of replicate experimentally evolved populations of Streptococcus pneumoniae propagated by repeated murine nasal colonization with the aim of identifying gene products under strong selection as well as the population-genetic dynamics of infection cycles. Frameshift mutations in one gene, dltB, responsible for incorporation of D-alanine into teichoic acids on the bacterial surface, evolved repeatedly and swept to high frequency. Targeted deletions of dltB produced a fitness advantage during initial nasal colonization coupled with a corresponding fitness disadvantage in the lungs during pulmonary infection. The underlying mechanism behind the fitness tradeoff between these two niches was found to be enhanced adherence to respiratory cells balanced by increased sensitivity to host-derived antimicrobial peptides, a finding recapitulated in the murine model. Additional mutations were also selected that are predicted to affect trace metal transport, central metabolism and regulation of biofilm production and competence. These data indicate that experimental evolution can be applied to murine models of pathogenesis to gain insight into organism-specific tissue tropisms.ImportanceEvolution is a powerful force that can be experimentally harnessed to gain insight into how populations evolve in response to selective pressures. Herein we tested the applicability of experimental evolutionary approaches to gain insight into how the major human pathogen Streptococcus pneumoniae responds to repeated colonization events using a murine model. These studies revealed the population dynamics of repeated colonization events and demonstrated that in vivo experimental evolution resulted in highly reproducible trajectories that reflect the environmental niche encountered during nasal colonization. Mutations impacting the surface charge of the bacteria were repeatedly selected during colonization and provided a fitness benefit in this niche that was counterbalanced by a corresponding fitness defect during lung infection. These data indicate that experimental evolution can be applied to models of pathogenesis to gain insight into organism-specific tissue tropisms.

In vivo pharmacodynamics of lascufloxacin and levofloxacin against Streptococcus pneumoniae and Prevotella intermedia in a pneumonia mixed-infection mouse model

Anaerobe ◽  
2021 ◽  
Vol 69 ◽  
pp. 102346
Author(s):  
Mao Hagihara ◽  
Hideo Kato ◽  
Yuichi Shibata ◽  
Daisuke Sakanashi ◽  
Nobuhiro Asai ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Mixed Infection ◽  
Prevotella Intermedia

scholarly journals Pneumococcal attachment to epithelial cells is enhanced by the secreted peptide VP1 via its control of hyaluronic acid processing

2019 ◽  
Author(s):  
Rolando A. Cuevas ◽  
Elnaz Ebrahimi ◽  
Ozcan Gazioglu ◽  
Hasan Yesilkaya ◽  
N. Luisa Hiller
Keyword(s):  
Hyaluronic Acid ◽  
Streptococcus Pneumoniae ◽  
Epithelial Cells ◽  
Nutrient Availability ◽  
Murine Model ◽  
Population Level ◽  
Host Cells ◽  
Human Pathogen ◽  
Biofilm Development

ABSTRACTThe Gram-positive bacterium Streptococcus pneumoniae (pneumococcus) is an important human pathogen. It can either asymptomatically colonize the nasopharynx or spread to other tissues to cause mild to severe diseases. Nasopharyngeal colonization is a prerequisite for all pneumococcal diseases. We describe a molecular pathway utilized by pneumococcus to adhere to host cells and promote colonization. We demonstrate that the secreted peptide VP1 enhances pneumococcal attachment to epithelial cells. Transcriptional studies reveal that VP1 triggers the expression of operons involved in the transport and metabolism of hyaluronic acid (HA), a glycosaminoglycan present in the host extracellular matrix. Genetic experiments in the pneumococcus reveal that HA processing locus (HAL) promotes attachment. Further, overexpression of HAL genes in the Δvp1 background, reveal that the influence of VP1 on attachment is mediated via its effect on HA. In addition, VP1 also enhances degradation of the HA polymer, in a process that depends on the HAL genes. siRNA experiments to knockdown host HA synthesis support this conclusion. In these knockdown cells, attachment of wild-type pneumococci is decreased, and VP1 and HAL genes no longer contribute to the attachment. Finally, experiments in a murine model of colonization reveal that VP1 and HAL genes are significant contributors to colonization. Our working model, which combines our previous and current work, is that changes in nutrient availability that influence CodY and Rgg144 lead to changes in the levels of VP1. In turn, VP1 controls the expression of a genomic region involved in the transport and metabolism of HA, and these HAL genes promote adherence in an HA-dependent manner. VP1 is encoded by a core gene, which is highly induced in vivo and is a major contributor to host adhesion, biofilm development, colonization, and virulence. In conclusion, the VP1 peptide plays a central role in a pathway that connects nutrient availability, population-level signaling, adhesion, biofilm formation, colonization, and virulence.AUTHOR SUMMARYStreptococcus pneumoniae (the pneumococcus) is a major human pathogen. This bacterium asymptomatically colonizes the human upper respiratory tract from where it can disseminate to other tissues causing mild to severe disease. Colonization is a prerequisite for dissemination and disease, such that the molecules that control colonization are high-value candidates for therapeutic interventions. Pneumococcal colonization is a population-level response, which requires attachment to host cells and biofilm development. VP1 is a signaling peptide, highly induced in the presence of host cells and in vivo, promotes biofilm development, and serves as a potent virulence determinant. In this study, we build on the molecular mechanism of VP1 function to reveal novel bacterial and host molecules that enhance adherence and colonization. Our findings suggest that host hyaluronic acid serves as an anchor for pneumococcal cells, and that genes involved in the transport and metabolism of HA promote adherence. These genes are triggered by VP1, which in turn, is controlled by regulators that respond to nutrient status of the host. Finally, our results are strongly supported by studies in a murine model of colonization. We propose that VP1 serves as a marker for colonization and a target for drug design.

scholarly journals In Vivo Efficacy of Trovafloxacin against Bacteroides fragilis in Mixed Infection with either Escherichia coli or a Vancomycin-Resistant Strain of Enterococcus faecium in an Established-Abscess Murine Model

2001 ◽  
Vol 45 (5) ◽  
pp. 1394-1401 ◽  
Author(s):  
Lorna E. T. Stearne ◽  
Inge C. Gyssens ◽  
Wil H. F. Goessens ◽  
Johan W. Mouton ◽  
Wim J. G. Oyen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Mixed Infection ◽  
Murine Model ◽  
Enterococcus Faecium ◽  
Bacteroides Fragilis ◽  
Time Curve ◽  
Bacterial Counts ◽  
E Coli ◽  
Vancomycin Resistant

ABSTRACT The pharmacodynamic and pharmacokinetic properties of trovafloxacin were studied in a standardized murine model of established subcutaneous abscesses. Daily dosing regimens of 37.5 to 300 mg/kg every 8 h (q8h) or every 24 h (q24h) were started 3 days after inoculation with mixtures containing either Bacteroides fragilis-Escherichia coli-autoclaved cecal contents (ACC) or B. fragilis–vancomycin-resistant Enterococcus faecium(VREF)–ACC. Treatment was continued for 3 or 5 days. The efficacy of treatment was determined by the decrease in abscess bacterial counts and abscess weights, as well as by the reduction in inflammation (biodistribution of 99mTc-HYNIC immunoglobulin G) compared to saline-treated controls. Trovafloxacin showed a significant dose-response effect on the bacterial counts, weight, and inflammation of B. fragilis-E. coli abscesses after 3 and/or 5 days of treatment. A maximum 3.4 and 3.1 log10 reduction in CFU/abscess in the respective B. fragilis and E. coli bacterial counts was attained after 5 days of treatment with daily doses of 300 mg/kg. The peak serum concentration was more predictive for effect than the area under the concentration-time curve. The C max was the pharmacodynamic index most predictive for success, and the efficacy of the q24h regimens was significantly better than the q8h regimens. The antibiotic was ineffective against the VREF in mixed infection with B. fragilis, while the killing of the anaerobe in the same combination was significantly less than in the E. colicombination (P < 0.05). We conclude that this is a useful model for studying the activity of antimicrobials for the treatment of small (<1-cm), undrainable, mixed-infection abscesses. In addition, we have shown for the first time that a decrease in bacterial numbers also leads to a reduction in both abscess weight and inflammation.

In vivo imaging reveals prostate pathology in the PTEN knockout murine model of prostate cancer

2016 ◽  
Author(s):  
Alysha Bhatti ◽  
Almeida Gilberto Serrano de ◽  
Serena Tommasini Ghelfi ◽  
Alwyn Dart ◽  
Anabel Varela-Carver ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Murine Model ◽  
In Vivo Imaging

255-LB: Impaired Gsa/cAMP Signaling Exclusive to Pancreatic ß-Cells Exhibits a Unique Urinary Metabolome via Nontargeted Metabolomics in a Murine Model of Diabetes In Vivo

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 255-LB
Author(s):  
AMRO ILAIWY ◽  
MEGAN CAPOZZI ◽  
JENNIFER L. BROWN ◽  
DAVID D’ALESSIO ◽  
JONATHAN CAMPBELL
Keyword(s):  
Murine Model ◽  
Camp Signaling

scholarly journals In vivo evaluation of a recombinant N-acylhomoserine lactonase formulated in a hydrogel using a murine model infected with MDR Pseudomonas aeruginosa clinical isolate, CCASUP2

AMB Express ◽  
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masarra M. Sakr ◽  
Walid F. Elkhatib ◽  
Khaled M. Aboshanab ◽  
Eman M. Mantawy ◽  
Mahmoud A. Yassien ◽  
...  
Keyword(s):  
Survival Rate ◽  
Murine Model ◽  
Histopathological Examination ◽  
Healing Process ◽  
Bacterial Count ◽  
Treated Group ◽  
Control Group ◽  
In Vivo Evaluation ◽  
Systemic Spread

AbstractFailure in the treatment of P. aeruginosa, due to its broad spectrum of resistance, has been associated with increased patient mortality. One alternative approach for infection control is quorum quenching which was found to decrease virulence of such pathogen. In this study, the efficiency of a recombinant Ahl-1 lactonase formulated as a hydrogel was investigated to control the infection of multidrug resistant (MDR) P. aeruginosa infected burn using a murine model. The recombinant N-acylhomoserine lactonase (Ahl-1) was formulated as a hydrogel. To test its ability to control the infection of MDR P. aeruginosa, a thermal injury model was used. Survival rate, and systemic spread of the infection were evaluated. Histopathological examination of the animal dorsal skin was also done for monitoring the healing and cellular changes at the site of infection. Survival rate in the treated group was 100% relative to 40% in the control group. A decrease of up to 3 logs of bacterial count in the blood samples of the treated animals relative to the control group and a decrease of up to 4 logs and 2.3 logs of bacteria in lung and liver samples, respectively were observed. Histopathological examination revealed more enhanced healing process in the treated group. Accordingly, by promoting healing of infected MDR P. aeruginosa burn and by reducing systemic spread of the infection as well as decreasing mortality rate, Ahl-1 hydrogel application is a promising strategy that can be used to combat and control P. aeruginosa burn infections.

scholarly journals Preclinical Studies in Anti-Trypanosomatidae Drug Development

2021 ◽  
Vol 14 (7) ◽  
pp. 644
Author(s):  
Cintya Perdomo ◽  
Elena Aguilera ◽  
Ileana Corvo ◽  
Paula Faral-Tello ◽  
Elva Serna ◽  
...  
Keyword(s):  
Rural Communities ◽  
Chagas Disease ◽  
Murine Model ◽  
Mammalian Cells ◽  
Drug Candidate ◽  
Murine Macrophages ◽  
Causative Agents ◽  
Trypanosomatid Parasites

The trypanosomatid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania are the causative agents of human African trypanosomiasis, Chagas Disease and Leishmaniasis, respectively. These infections primarily affect poor, rural communities in the developing world, and are responsible for trapping sufferers and their families in a disease/poverty cycle. The development of new chemotherapies is a priority given that existing drug treatments are problematic. In our search for novel anti-trypanosomatid agents, we assess the growth-inhibitory properties of >450 compounds from in-house and/or “Pathogen Box” (PBox) libraries against L. infantum, L. amazonensis, L.braziliensis, T. cruzi and T. brucei and evaluate the toxicities of the most promising agents towards murine macrophages. Screens using the in-house series identified 17 structures with activity against and selective toward Leishmania: Compounds displayed 50% inhibitory concentrations between 0.09 and 25 μM and had selectivity index values >10. For the PBox library, ~20% of chemicals exhibited anti-parasitic properties including five structures whose activity against L. infantum had not been reported before. These five compounds displayed no toxicity towards murine macrophages over the range tested with three being active in an in vivo murine model of the cutaneous disease, with 100% survival of infected animals. Additionally, the oral combination of three of them in the in vivo Chagas disease murine model demonstrated full control of the parasitemia. Interestingly, phenotyping revealed that the reference strain responds differently to the five PBox-derived chemicals relative to parasites isolated from a dog. Together, our data identified one drug candidate that displays activity against Leishmania and other Trypanosomatidae in vitro and in vivo, while exhibiting low toxicity to cultured mammalian cells and low in vivo acute toxicity.

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