Evaluation of LBM415 (NVP PDF-713), a Novel Peptide Deformylase Inhibitor, for Treatment of Experimental Mycoplasma pneumoniae Pneumonia

Abstract

Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. We evaluated the efficacy of LBM415, a novel peptide deformylase inhibitor antimicrobial agent, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were intranasally inoculated once with 10 7 CFU of M. pneumoniae. Groups of mice were treated with LBM415 (50 mg/kg of body weight) or placebo subcutaneously daily for 13 days, starting 24 h after inoculation. Groups of mice were evaluated at the baseline; at days of treatment 1, 3, 6, and 13; and at 7 days after treatment. The MIC of LBM415 against M. pneumoniae was <0.005 g/ml. LBM415-treated mice had significantly lower bronchoalveolar lavage fluid M. pneumoniae concentrations than placebo-treated mice on days 6 and 13 of treatment. Compared with placebo treatment, therapy with LBM415 significantly decreased lung histopathology scores at days 3, 6, and 13 of treatment and at 7 days after treatment. Airway obstruction was significantly lower in LBM415-treated mice than in placebotreated mice on days 1, 3, and 6 of treatment and after 7 days of therapy, while airway hyperresponsiveness was significantly lower only on day 3 of therapy. The bronchoalveolar lavage fluid concentrations of tumor necrosis factor alpha, gamma interferon (IFN-␥), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1␣, monokine induced by IFN-␥, and IFN-inducible protein 10 were significantly reduced in LBM415-treated mice compared with the levels in placebo-treated mice. There were no differences in the bronchoalveolar lavage fluid concentrations of granulocyte-macrophage colonystimulating factor, IL-1␤, IL-2, IL-4, IL-5, and IL-10 between the two groups of mice. LBM415 therapy had beneficial microbiologic, histologic, respiratory, and immunologic effects on acute murine M. pneumoniae pneumonia.Mycoplasma pneumoniae is an important cause of upper and lower respiratory tract infections in children and adults and is responsible for as many as 40% of cases of community-acquired pneumonia (7,15,28,33). Tetracyclines, macrolides, ketolides, and fluoroquinolones have in vitro activities against M. pneumoniae (43, 44). Most of these agents are primarily bacteriostatic for M. pneumoniae, and only the fluoroquinolones have been shown to be bactericidal (10, 42). While M. pneumoniae can be cultured from respiratory secretions for long periods after acute infection even after appropriate antimicrobial therapy, most antibiotics produce satisfactory clinical results, with a significant reduction in the duration of symptoms compared with no treatment (30,36). Macrolide and related antibiotics are generally considered the therapy of choice for M. pneumoniae infections in children and adults. Strains with acquired resistance to macrolides have rarely been described (29).LBM415 (previously known as NVP PDF-713) is a novel inhibitor of the bacterial enzyme peptide deformylase (PDF) and has been documented to have in vitro activity against...

Respiratory Tract Infection withMycoplasma pneumoniaein Interleukin-12 Knockout Mice Results in Improved Bacterial Clearance and Reduced Pulmonary Inflammation

“…A trend for a decrease in the proinflammatory cytokine TNF-␣ was also noted. In previous studies TNF-␣ has been directly associated with M. pneumoniae disease severity (12,13,17), and its lower concentrations in the BAL fluid may have contributed to the decreased histologic lung inflammation in the IL-12 KO mice. We also found a trend for a decrease in the anti-inflammatory cytokine IL-10 in the IL-12 KO mice; this could be explained by the fact that IL-10 is a known negative feedback regulator of IL-12 production from phagocytic and dendritic cells (50).…”

“…IL-12 is a heterodimeric cytokine that is composed of two subunits (p40 and p35) and is produced by antigen-presenting cells (phagocytes and dendritic cells) and targets natural killer and the T cells inducing the production of gamma interferon (IFN-␥; the Th1 effector cytokine) (15,26,37). To evaluate the role of IL-12 in the pathogenesis of M. pneumoniae respiratory infection, we studied the effect of IL-12 deletion on airway dysfunction and inflammation using IL-12 (p35) knockout animals in our established murine model of M. pneumoniae pneumonia (12,13,17,18). …”

Intranasal Interleukin-12 Therapy InhibitsMycoplasma pneumoniaeClearance and Sustains Airway Obstruction in Murine Pneumonia

“…Murine model studies have shown that M. pneumoniae infection induces a Th1 cytokine response in the lungs, manifested by elevated concentrations of IL-12 and IFN-␥ with associated airway obstruction (AO), airway hyperreactivity (AHR), and lung histologic inflammation (12,18). In a recent study utilizing IL-12 (p35) knockout (KO) mice in our established murine model of M. pneumoniae respiratory infection, we demonstrated, somewhat surprisingly, that the absence of IL-12 significantly reduced disease severity, as assessed by pulmonary histopathology, airway function, and quantitative cultures (36).To further study the role of IL-12, we evaluated the effect of intranasal IL-12 treatment on airway dysfunction and inflammation in our established murine model of M. pneumoniae pneumonia (12,13,18,19). …”

“…To further study the role of IL-12, we evaluated the effect of intranasal IL-12 treatment on airway dysfunction and inflammation in our established murine model of M. pneumoniae pneumonia (12,13,18,19).…”

Identification of Crucial Amino Acids of Bacterial Peptide Deformylases Affecting Enzymatic Activity in Response to Oxidative Stress

“…In fact, removal of the formyl group of the first methionine is mandatory for its subsequent excision in the process of maturation of the polypeptide chain (7); therefore, PDFs are known to be essential for bacterial survival (8)(9)(10). Also, in pathogenic bacteria, PDF is a promising and wellexplored drug target (11)(12)(13).…”