Evaluation of LBM415 (NVP PDF-713), a novel peptide deformylase inhibitor, for treatment of experimental Mycoplasma pneumoniae pneumonia.
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 microg/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 placebo-treated 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-gamma), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, monokine induced by IFN-gamma, 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 colony-stimulating factor, IL-1beta, 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.
Fonseca-Aten
Monica
M
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, 75390-9063, USA. Monica.Fonseca-Aten@utsouthwestern.edu
Salvatore
Christine M
CM
Mejías
Asunción
A
Ríos
Ana M
AM
Chávez-Bueno
Susana
S
Katz
Kathy
K
Gómez
Ana M
AM
McCracken
George H
GH
Hardy
R Doug
RD
D000402:Airway Obstruction / Q000503:physiopathology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000382:microbiology; D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009177:Mycoplasma pneumoniae; D010455:Peptides / Q000627:therapeutic use*; D010991:Plethysmography; D011019:Pneumonia, Mycoplasma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013997:Time Factors
D018925:Chemokines; D016207:Cytokines; C487638:NVP PDF 713; D010455:Peptides; D000581:Amidohydrolases; C084507:peptide deformylase