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The Biosynthetic Monophosphoryl Lipid A Enhances the Therapeutic Outcome of Antibiotic Therapy in Pneumococcal Pneumonia.

Abstract : Alternative treatment strategies against bacterial infections are required to decrease the use of antibiotics. This study tested the hypothesis that stimulation of the innate immune receptor Toll-like receptor 4 can be combined with antibiotics to improve the treatment of invasive pneumonia. The efficacy of the biosynthetic monophosphoryl lipid A (MPLA), a clinically approved Toll-like receptor 4 activator, was tested in a mouse model of Streptococcus pneumoniae respiratory infection. Interestingly, administration of amoxicillin or MPLA decreased 400- to 11 000-fold the bacterial load in the lungs and spleen but did not enhance survival compared to mock treatment. The single administration of a combination of MPLA and amoxicillin further reduced 10- to 18-fold the bacterial colonization and invasion and significantly improved protection against lethal disease. The combined administration of MPLA and amoxicillin in a context of infection was associated with transient increase of the serum concentrations of amoxicillin and pro-inflammatory cytokines and chemokines as well as the expression of immune genes in lung tissue. Remarkably, the systemic and lung immune activation extended beyond amoxicillin elimination, suggesting a two-step and cooperative anti-infective effect, i.e., rapid antibiotic-mediated alteration of bacteria and a long-lasting impact through mucosal and systemic immunity. Our proof-of-concept study demonstrated for the first time that boosting Toll-like receptor 4 signaling can synergize with antibiotics in order to increase the efficacy of therapy of bacterial pneumonia, thereby in fine reducing the dose or regimen of antibiotics.
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https://www.hal.inserm.fr/inserm-03288018
Contributor : Jean-Claude Sirard <>
Submitted on : Thursday, July 29, 2021 - 12:33:40 PM
Last modification on : Friday, July 30, 2021 - 10:07:45 AM

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Fiordiligie Casilag, Laura Matarazzo, Sebastian Franck, Martin Figeac, Robin Michelet, et al.. The Biosynthetic Monophosphoryl Lipid A Enhances the Therapeutic Outcome of Antibiotic Therapy in Pneumococcal Pneumonia.. ACS Infectious Diseases, American Chemical Society, 2021, Online ahead of print. ⟨10.1021/acsinfecdis.1c00176⟩. ⟨inserm-03288018⟩

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