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Impact of Cethromycin (ABT-773) Therapy on Microbiological, Histologic, Immunologic, and Respiratory Indices in a Murine Model of Mycoplasma pneumoniae Lower Respiratory Infection. Ana María Ríos, 2004.Mycoplasma pneumoniae is a major etiologic agent of acute lower respiratory infections . We evaluated the antimicrobial and immunologic effects of cethromycin (ABT-773), a ketolide antibiotic, for the treatment of M . pneumoniae pneumonia in a mouse model . Eight-week-old BALB/c mice were inoculated intranasally once with 106 CFU of M . pneumoniae on day 0 . Treatment was started 24 h after inoculation . Groups of mice were treated subcutaneously with cethromycin at 25 mg/kg of body weight or with placebo daily until sacrifice . Five to ten mice per group were evaluated at days 1, 4, 7, and 10 after inoculation . Outcome variables included bronchoalveolar lavage (BAL) for M . pneumoniae quantitative culture and cytokine and chemokine concentration determinations by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-  ], gamma interferon [IFN- ], interleukin-1ß [IL-1ß], IL-2, IL-4, IL-12, granulocyte-macrophage colony-stimulating factor, IL-8, monocyte chemoattractant protein 1 [MCP-1], and macrophage inflammatory protein 1 [MIP-1]), histopathologic score of the lungs (HPS), and pulmonary function tests (PFT) using whole-body, unrestrained plethysmography at the baseline and post-methacholine exposure as indicators of airway obstruction (AO) and airway hyperresponsiveness (AHR), respectively . The cethromycin-treated mice had a greater reduction in M . pneumoniae culture titers than placebo-treated mice, reaching statistical significance on days 7 and 10 (P < 0.05) . HPS was significantly reduced in cethromycin-treated mice compared with placebo-treated mice on days 4, 7, and 10 (P < 0.05) . Cytokine concentrations in BAL samples were reduced in mice that received cethromycin, and the differences were statistically significant for 7 of the 10 cytokines measured (TNF-, IFN-, IL-1ß, IL-8, IL-12, MCP-1, and MIP-1) on day 4 (P < 0.05) . PFT values were improved in the cethromycin-treated mice, with AO and AHR significantly reduced on day 4 (P < 0.05) . In this mouse model, treatment with cethromycin significantly reduced M . pneumoniae culture titers in BAL samples, cytokine and chemokine concentrations in BAL samples, histologic inflammation in the lungs, and disease severity as defined by AO and AHR .
The Crystal Structure of the Phosphorylation Domain in PhoP Reveals a Functional Tandem Association Mediated by an Asymmetric Interface. Catherine Birck, 2003.PhoP from Bacillus subtilis belongs to the OmpR subfamily of response regulators . It regulates the transcription of several operons and participates in a signal transduction network that controls adaptation of the bacteria to phosphate deficiency . The receiver domains of two members of this subfamily, PhoB from Escherichia coli and DrrD from Thermotoga maritima, have been structurally characterized . These modules have similar overall folds but display remarkable differences in the conformation of the ß4-  4 and
4 regions . The crystal structure of the receiver domain of PhoP (PhoPN) described in this paper illustrates yet another geometry in this region . Another major issue of the structure determination is the dimeric state of the protein and the novel mode of association between receiver domains . The protein-protein interface is provided by two different surfaces from each protomer, and the tandem unit formed through this asymmetric interface leaves free interaction surfaces . This design is well suited for further association of PhoP dimers to form oligomeric structures . The interprotein interface buries 970 Å2 from solvent and mostly involves interactions between charged residues . As described in the accompanying paper, mutations of a single residue in one salt bridge shielded from solvent prevented dimerization of the unphosphorylated and phosphorylated response regulator and had drastic functional consequences . The three structurally documented members of the OmpR family (PhoB, DrrD, and PhoP) provide a framework to consider possible relationships between structural features and sequence signatures in critical regions of the receiver domains .
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