Identification of (+)-erythro-mefloquine as an active enantiomer with greater efficacy than mefloquine against Mycobacterium avium infection in mice.

Infection caused by Mycobacterium avium is common in AIDS patients who do not receive treatment with highly active antiretroviral therapy (HAART) or who develop resistance to anti-HIV therapy. Mefloquine, a racemic mixture used for malaria prophylaxis and treatment, is bactericidal against M. avium in mice.

The efficacy of clarithromycin and the bicyclolide EDP-420 against Mycobacterium avium in a mouse model of pulmonary infection.

Lung disease caused by Mycobacterium avium complex (MAC) is increasing in prevalence. MAC disease occurs in patients with chronic preexisting obstructive pulmonary diseases but is also diagnosed in individuals with no history of lung pathology or identifiable immune defect. Histologically, the disease is characterized by either the development of nodular granulomatous lesions in the peribronchial region or cavitary peripheral disease in smokers.

Identification of Mycobacterium avium genes that affect invasion of the intestinal epithelium.

Invasion of intestinal mucosa of the host by Mycobacterium avium is a critical step in pathogenesis and likely involves several different bacterial proteins, lipids, glycoproteins, and/or glycolipids. Through the screening of an M. avium genomic library in Mycobacterium smegmatis, we have identified a number of M.

A Mycobacterium avium PPE gene is associated with the ability of the bacterium to grow in macrophages and virulence in mice.

PPE and PE gene families, which encode numerous proteins of unknown function, account for 10% of Mycobacterium tuberculosis genome. Mycobacterium avium genome has similar PPE and PE gene families. Using a temperature-sensitive phage phAE94 transposon mutagenesis system, a M.

Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell's endosomal system.

Mycobacterium avium and Mycobacterium tuberculosis are human pathogens that infect and replicate within macrophages. Both organisms live in phagosomes that fail to fuse with lysosomes and have adapted their lifestyle to accommodate the changing environment within the endosomal system. Among the many environmental factors that could influence expression of bacterial genes are the concentrations of single elements within the phagosomes.

Differential gene expression in mononuclear phagocytes infected with pathogenic and non-pathogenic mycobacteria.

The pathogenic mycobacteria are an insidious group of bacterial pathogens that cause the deaths of millions of people every year. One of the reasons these pathogens are so successful is that they are able to invade and replicate within host macrophages, one of the first lines of defence against intruding pathogens. In contrast, non-pathogenic mycobacteria, such as Mycobacterium smegmatis are killed rapidly by macrophages.

Mycobacterium tuberculosis infection causes different levels of apoptosis and necrosis in human macrophages and alveolar epithelial cells.

Mycobacterium tuberculosis interacts with macrophages and epithelial cells in the alveolar space of the lung, where it is able to invade and replicate in both cell types. M. tuberculosis-associated cytotoxicity to these cells has been well documented, but the mechanisms of host cell death are not well understood.

Thiosemicarbazole (thiacetazone-like) compound with activity against Mycobacterium avium in mice.

In vitro screening of thiacetazone derivatives indicated that two derivatives, SRI-286 and SRI-224, inhibited a panel of 25 Mycobacterium avium complex (MAC) isolates at concentrations of 2 micro g/ml or lower. In mice, SRI-224 and thiacetazone had no significant activity against the MAC in livers and spleens, but treatment with SRI-286 resulted in significant reduction of bacterial loads in livers and spleens. A combination of SRI-286 and moxifloxacin was significantly more active than single drug regimens in liver and spleen.

Mefloquine, moxifloxacin, and ethambutol are a triple-drug alternative to macrolide-containing regimens for treatment of Mycobacterium avium disease.

Macrolides are the core of effective drug regimens for the treatment of Mycobacterium avium complex (MAC) disease. Mefloquine (MFQ), moxifloxacin (MXF), and ethambutol (EMB), in combination, were evaluated against both clarithromycin-resistant (CLR-R) and CLR-susceptible (CLR-S) MAC; MFQ (40 mg/kg), MXF (100 mg/kg), or EMB (100 mg/kg/day) was given to mice for 4 weeks. MFQ was bactericidal, whereas MXF and EMB were bacteriostatic against both MAC 101 CLR-S and CLR-R.

Mycobacterium tuberculosis uptake by recipient host macrophages is influenced by environmental conditions in the granuloma of the infectious individual and is associated with impaired production of interleukin-12 and tumor necrosis factor alpha.

Transmission of Mycobacterium tuberculosis from one individual to another usually is associated with episodes of coughing. The bacteria leave the environment of the lung cavity of the infected person and travel in droplets to reach the recipient's respiratory tract. Therefore, at the time that the bacteria encounter alveolar cells (macrophages and epithelial cells) in the new host, they express virulence determinants that are regulated by the environmental conditions in the infected person.

Mycobacterium avium infection of macrophages results in progressive suppression of interleukin-12 production in vitro and in vivo.

Interleukin-12 (IL-12) has been shown to have an important role in the host defense against Mycobacterium avium. We sought to determine if human monocyte-derived macrophages produce IL-12 upon M. avium infection.

The efficiency of the translocation of Mycobacterium tuberculosis across a bilayer of epithelial and endothelial cells as a model of the alveolar wall is a consequence of transport within mononuclear phagocytes and invasion of alveolar epithelial cells.

The mechanism(s) by which Mycobacterium tuberculosis crosses the alveolar wall to establish infection in the lung is not well known. In an attempt to better understand the mechanism of translocation and create a model to study the different stages of bacterial crossing through the alveolar wall, we established a two-layer transwell system. M.

Perspective on animal models: chronic intracellular infections.

Systemic human disease caused by organisms of the Mycobacterium avium-Mycobacterium intracellulare complex (MAC) represent a chronic intracellular infection in human hosts who are usually immunocompromised. To develop improved treatment and prophylaxis, and to obtain a better understanding of pathogenesis, we studied the beige mouse (C57 beige(+)/beige(+)) challenged orally or intravenously with a human isolate that causes lethal disease in patients with AIDS (MAC 101, serovar 1). Encouraging anti-MAC studies in animals, as reviewed here, should provide the basis for considering human trials with a promising agent.

Characterization of IS666, a newly described insertion element of Mycobacterium avium.

The insertion sequence IS666 was isolated from Mycobacterium avium strain 101. IS666 is a 1474 bp insertion sequence belonging to the IS256 family, that includes IS6120 from Mycobacterium smegmatis, IS1166 and IS1295 from Rhodococcus sp. IGTS8, IST2 from Thiobacillus ferrooxidans, IS256 from Staphylococcus aureus, and ISRm3 from Rhizobium meliloti.

Telithromycin is active against Mycobacterium avium in mice despite lacking significant activity in standard in vitro and macrophage assays and is associated with low frequency of resistance during treatment.

The activity of telithromycin, a new ketolide, was evaluated in vitro and in vivo against Mycobacterium avium complex (MAC) strains. The MIC of telithromycin for several M. avium isolates obtained from the blood of AIDS patients ranged from 16 to >128 microg/ml (MIC at which 90% of isolates are inhibited, >128 microg/ml), and the compound did show activity in the macrophage system at concentrations greater than 8 or 16 microg/ml, but this was dependent on the MAC strain used.

Infection of mice with Mycobacterium avium primes CD8+ lymphocytes for apoptosis upon exposure to macrophages.

Mycobacterial infection is associated with granuloma formation in which the presence of apoptosis has been recognized. The role of CD4+ T and CD8+ T cells in host protection against mycobacterial infections has been demonstrated. Previous studies, however, have shown that CD8+ T cells have a limited role in host defense against Mycobacterium avium infection, and we hypothesize that M.

Characterization and expression of secA in Mycobacterium avium.

Mycobacterium avium is both a pathogen that infects several hosts such as humans, pigs, and birds, as well as a microorganism that is encountered in environmental sources (soil and water). Protein secretion by the bacterium is likely to influence its ability to overcome adverse and competitive conditions both within or outside the host. Using a combination of cloning and information available in the databank, we characterized the secA gene from M.

Phenotypic consequences of red-white colony type variation in Mycobacterium avium.

Mycobacterium avium undergoes reversible morphotypic switching between the virulent transparent colony type and the less virulent opaque colony type. A new morphotypic switch in M. avium, termed red-white, that becomes visible when opaque colonies of clinical isolates are grown on agar media containing Congo red, was recently described.

Cellular and molecular mechanisms of internalization of mycobacteria by host cells.

Mycobacteria are intracellular pathogens capable of invading mononuclear phagocytes, mucosal epithelial cells (including M cells) and Schwann cells. To enter cells, mycobacteria have been shown to interact with several molecules on macrophage and epithelial cell surfaces. This suggests adaptation to the host environment.

Mycobacterium avium enters intestinal epithelial cells through the apical membrane, but not by the basolateral surface, activates small GTPase Rho and, once within epithelial cells, expresses an invasive phenotype.

Mycobacterium avium is a common pathogen in AIDS patients that is primarily (but not exclusively) acquired through the gastrointestinal tract, leading to the development of bacteraemia and disseminated disease. To cause infection through the gut, binding and invasion of the intestinal epithelial barrier are required. To characterize this process further, we determined the cell surface(s) (basolateral vs.

Mechanisms of Mycobacterium avium pathogenesis.

Infections caused by Mycobacterium avium are common in AIDS patients and patients with chronic lung diseases. The bacterium can be acquired both through the intestinal route and respiratory route. M.

Mycobacterium avium invades the intestinal mucosa primarily by interacting with enterocytes.

Previous studies have demonstrated that Mycobacterium avium can invade intestinal epithelial cells both in vitro and in vivo. When given to mice orally, M. avium preferentially interacts with the intestinal mucosa at the terminal ileum.

Activity of moxifloxacin by itself and in combination with ethambutol, rifabutin, and azithromycin in vitro and in vivo against Mycobacterium avium.

Moxifloxacin activity against Mycobacterium avium complex (MAC) was evaluated in vitro against 25 strains. The MIC was determined to range from 0.125 to 2.