In vivo efficacy of dendrimer–methylprednisolone conjugate formulation for the treatment of lung inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

Download Full-text

Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide

Nature Communications ◽

10.1038/s41467-021-24127-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pierre Santucci ◽

Daniel J. Greenwood ◽

Antony Fearns ◽

Kai Chen ◽

Haibo Jiang ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Host Cell ◽

Combination Chemotherapy ◽

In Vitro Activity ◽

In Vivo Efficacy ◽

Human Macrophages ◽

Ion Microscopy ◽

Intracellular Localisation

AbstractTo be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.

Download Full-text

P074 In vitro and in vivo efficacy of linezolid on Treponema pallidum, the syphilis agent

10.1136/sextrans-2021-sti.208 ◽

2021 ◽

Author(s):

L Giacani ◽

A Haynes ◽

M Vall Mayans ◽

M Ubals Cazorla ◽

C Nieto ◽

...

Keyword(s):

Treponema Pallidum ◽

In Vivo Efficacy

Download Full-text

Efficacy of a novel lantibiotic, CMB001, against MRSA

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab040 ◽

2021 ◽

Author(s):

Jerzy Karczewski ◽

Christine M Brown ◽

Yukari Maezato ◽

Stephen P Krasucki ◽

Stephen J Streatfield

Keyword(s):

Antibacterial Activity ◽

Pharmacokinetic Analysis ◽

Maximum Tolerable Dose ◽

In Vivo Efficacy ◽

Clostridioides Difficile ◽

Alternative Treatment Option ◽

Significant Damage ◽

Tolerable Dose

Abstract Objectives To evaluate the efficacy of a novel lantibiotic, CMB001, against MRSA biofilms in vitro and in an in vivo experimental model of bacterial infection. Methods Antibacterial activity of CMB001 was measured in vitro after its exposure to whole blood or to platelet-poor plasma. In vitro efficacy of CMB001 against a Staphylococcus aureus biofilm was studied using scanning electron microscopy. The maximum tolerable dose in mice was determined and a preliminary pharmacokinetic analysis for CMB001 was performed in mice. In vivo efficacy was evaluated in a neutropenic mouse thigh model of infection. Results CMB001 maintained its antibacterial activity in the presence of blood or plasma for up to 24 h at 37°C. CMB001 efficiently killed S. aureus within the biofilm by causing significant damage to the bacterial cell wall. The maximum tolerable dose in mice was established to be 10 mg/kg and could be increased to 30 mg/kg in mice pretreated with antihistamines. In neutropenic mice infected with MRSA, treatment with CMB001 reduced the bacterial burden with an efficacy equivalent to that of vancomycin. Conclusions CMB001 offers potential as an alternative treatment option to combat MRSA. It will be of interest to evaluate the in vivo efficacy of CMB001 against infections caused by other pathogens, including Clostridioides difficile and Acinetobacter baumannii, and to expand its pharmacokinetic/pharmacodynamic parameters and safety profile.

Download Full-text