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Synergistic effect of romurtide with ampicillin against pneumococcal pneumonia in mice
R Nakajima1, K Namba, Y Ishida
1Exploratory Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Abstract:
The anti-infective activity of romurtide, a synthetic muramyl dipeptide (MDP) derivative, was evaluated in experimental pneumococcal pneumonia in mice deficient in the third component of complement (C3). The compound was found to be effective against the pneumonia in combination with subcutaneous ampicillin (ABPC). This synergistic effect of romurtide with ABPC was most pronounced when the compound was administered subcutaneously 1 day before infection. Romurtide alone, however, was not effective, irrespective of its treatment timing. Similarly, consecutive treatment with ABPC alone failed to kill pneumococci in the lungs completely, and resultant regrowth of the organisms provoked purulent pneumonia. In contrast, the combination treatment of romurtide with ABPC successfully prevented most of the mice from the purulent pneumonia: the initial infiltration of resident alveolar macrophages and subsequent accumulation of macrophages were observed in the pneumonic foci. In accordance with the occurrence of these cellular responses in the lungs, pneumococci were successfully eliminated from the lungs in mice treated with romurtide in combination with ABPC. Thus, romurtide was suggested to promote recovery of the mice with pneumococcal pneumonia by activating resident and accumulated macrophages in the pneumonic foci to eliminate pneumococci from the lung.
Insights
Romurtide, a synthetic muramyl dipeptide (MDP) derivative, enhances ampicillin
Area of Science:
- Immunology
- Pharmacology
- Microbiology
Background:
- Pneumococcal pneumonia poses a significant health challenge.
- Complement component 3 (C3) plays a role in host defense against Streptococcus pneumoniae.
- Muramyl dipeptide (MDP) derivatives are known for immunomodulatory properties.
Purpose of the Study:
- To evaluate the anti-infective activity of romurtide against experimental pneumococcal pneumonia.
- To investigate the synergistic effect of romurtide with ampicillin (ABPC) in a mouse model.
- To elucidate the mechanism of romurtide's action in enhancing host defense.
Main Methods:
- Experimental pneumococcal pneumonia was induced in mice deficient in complement component 3 (C3).
- Mice were treated with romurtide, ampicillin (ABPC), or a combination of both.
- Macrophage infiltration and bacterial load in the lungs were assessed.
Main Results:
- Romurtide demonstrated synergistic anti-infective activity when combined with subcutaneous ampicillin (ABPC).
- The combination therapy prevented purulent pneumonia and reduced bacterial regrowth compared to ABPC alone.
- Romurtide treatment promoted macrophage activation and infiltration in pneumonic lung foci.
Conclusions:
- Romurtide enhances the efficacy of ampicillin (ABPC) in treating experimental pneumococcal pneumonia.
- The synergistic effect is mediated by the activation of macrophages, leading to bacterial clearance.
- Romurtide shows potential as an adjunctive therapy for pneumococcal infections, particularly in complement-deficient states.