Respiratory tract infection is the third cause of death worldwide. Although antibiotics are recognized as an effective therapy, treatment is often associated with failure due to resistance to antibiotics. The pathogenic bacteria: Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae are the most relevant causes of pneumonia. Our proposal aims to develop non-traditional combination therapies to minimize treatment failure.
Because innate immunity is rapidly activated, is self-limiting, and involves a broad spectrum of effectors, it represents an ideal antimicrobial therapeutic target. Treatment with agonists of Toll-like receptor 4 (TLR4) or TLR5, innate sensors of microbial danger, improve clearance of mouse respiratory infections. Stimulation of peroxisome proliferator-activated receptor gamma (PPARg), a key inhibitor of pro-inflammatory responses reduces bacterial growth during pneumonia. Stimulating interleukin-22 reduces inflammation during flu infection and protects against secondary bacterial infection. Targeting both host innate immunity and pathogenic bacteria using antibiotics delivers a valuable solution to improve treatment of infections. The proof of concept in mouse models of pneumonia was shown by combining first-line antibiotic or ND-AB with a TLR5 agonist. ABIMMUNE aims at improving the treatment of respiratory infections by repurposing registered immunostimulatory drugs in combination therapies with ND-AB in order to attack pathogens in a manner that: <br />-activates innate antibacterial defenses in vulnerable patients <br />-is effective on bacteria resistant to first-line antibiotics <br />-decreases the emergence of antibiotic resistance <br /> <br />ABIMMUNE will target specifically cells or pathways of innate immunity including: <br />-phagocytes <br />-TLRs <br />-the autophagy regulator mTOR <br />-the inhibition of inflammation via PPARg <br /> <br />The combination therapies will be assessed on: <br />-clinical isolates of antibiotic-susceptible and -resistant bacteria <br />-mouse infection models of pneumonia with P. aeruginosa, K. pneumoniae, S. aureus, and S. pneumoniae. <br /> <br />Integrated pharmacometric modelling will use checkerboards, time-kill curves and a novel response surface analysis for defining the nature of interactions and the efficacy of ND-AB/immunomodulator combinations, as recently described by partners. ABIMMUNE experimental data will be used for the development of pharmacometric models and clinical trial simulation.
The first objective is to screen combination therapies based on in vitro antibacterial efficacy, immunological studies and pharmacokinetic/pharmacodynamic modelling.
The second objective is to demonstrate the proof-of-concept of increased efficacy of selected combination therapies compared to standalone treatments in validated mouse models of bacterial pneumonia.
The third objective is to assess the efficacy of combination therapies on clinical isolates resistant to first-line antibiotic or multidrug resistant bacteria and the impact on emergence of resistance to ND-AB and immunomodulators.
Selection of appropriate ND-AB and immunomodulators
Set up of airway epithelial cell-based assays of immune modulators
Set up of macrophage-based assays of immune modulators
Development of macrophage-based assays for PK/PD and for evaluation antibacterial activity with combinations of immunomodulators and ND-AB
In vitro checkerboard and time-kill curve assays of ND-AB and/or immune modulators and screening of combinations
In vivo analysis of immunostimulatory activities of immunomodulators
Analysis of antibacterial activity of a first selected drug combination in mouse S. pneumoniae and S. aureus pneumonia
Analysis of antibacterial activity of a second selected drug combination in mouse K. pneumoniae pneumonia
Modelling and simulation of activity of the combination therapies in clinical settings
Evaluation of combinations therapies in immune-suppressed conditions
Test the efficacy of combination therapies against antibiotic-resistant bacteria and emergence of resistance
Bacterial respiratory infections represent a real threat to public health worldwide, especially in hospital-acquired situations where patients frequently present several co-morbidity factors. Although antibiotics are recognized as the most effective therapy, treatments are often associated with failure due to bacteria that are resistant to multiple first-line antibiotics, and patients who are immune compromised.The proposal ABIMMUNE aims to enhance the therapeutic arsenal against respiratory infections. The idea is to combine Neglected and Disused AntiBiotics (ND-AB) with registered immune modulators that impact host innate immunity. ABIMMUNE will select (i) ND-AB that are not used as first-line antibiotics in standalone treatment of respiratory infections, and (ii) marketed immunostimulatory drugs that target distinct immune pathways including macrophage activation, neutrophil potentiation, immuno-metabolism, or pattern-recognition receptors.There are several advantages to this approach: first, antibacterial activity of innate immunity is independent of antibiotic-resistance. Second, it is difficult for the pathogen to develop resistance to innate immunity since this latter involves multiple killer cells and antibacterial molecules, and bacteria would have to develop an entirely new suite of interactions with the host. Third, targeting host innate immunity may reinstate some immune defense in vulnerable patients. Fourth, innate immunity and ND-AB may synergize to kill bacteria thereby allowing for dose reduction of ND-AB and potentially reducing side effects. Fifth, using ND-AB may globally dampen the proportion of bacteria resistant to first-line antibiotics, allowing their maintenance in clinics.These combination therapies will be tested in clinically relevant models of respiratory infections with the leading Gram-positive and Gram-negative bacteria causing community- and hospital-acquired pneumonia. ABIMMUNE will validate in vitro the proof-of-concept of additive or synergistic activity of ND-AB and immunostimulatory drugs with appropriate host target cells and collection of bacterial isolates. The impact on emergence and maintenance of resistance to first-line antibiotics and ND-AB will also be evaluated. Experiments will be accompanied by translational PK/PD modeling analyses to quantify the joint ND-AB/immune modulators interaction for selection of the most promising regimens for pneumonia in the context of immune vulnerability.
Monsieur Jean-Claude SIRARD (Institut Pasteur de Lille,Inserm U1019, Centre d'Infection et d'Immunité de Lille)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
FUB Freie Universität Berlin, Institut für Pharmazie
CONICET National Universtity of La Plata, Instituto de Estudios Inmunológicos y Fisiopatológicos
AMC Academic Medical Centre, University of Amsterdam; Centre of Experimental & Molecular Medicine
INSERM U1100 - CEPR Centre d'Etude des Pathologies Respiratoires, INSERM U1100, Faculté de Médecine de Tours
INSERM 1019 CIIL Institut Pasteur de Lille,Inserm U1019, Centre d'Infection et d'Immunité de Lille
Help of the ANR 380,590 euros
Beginning and duration of the scientific project: January 2016 - 36 Months