<i>Mycobacterium tuberculosis</i>
            in Macrophages: Effect of Certain Surfactants and Other Membrane-Active Compounds

Hart, P. D’Arcy

doi:10.1126/science.162.3854.686

Cited by 47 publications

(33 citation statements)

References 19 publications

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“…Importantly, however, the relevance of CD1-dependent T cells in Macrocyclon function in vivo was not properly addressed in our experiments; therefore, additional experiments using Rag or T-cell receptor ␣/␤ and ␥/␦ double-knockout mice are needed to clarify this issue. Our data are in line with previous reports on the action of Macrocyclon in murine macrophages (7) and confirm the notion that calixarenes principally enhance nonspecific innate immune defense mechanisms in murine macrophages. Previous work demonstrated that lipid metabo- lism is affected in Macrocyclon-treated cells and suggested that Macrocyclon antimycobacterial activity correlated with inhibition of triglyceride lipase and phospholipases (8); our results provide evidence that L-arginine metabolism and iNOS activity are required for Macrocyclon-induced antimycobacterial activity in murine macrophages.…”

Section: Discussionsupporting

confidence: 82%

“…The compound HOC was prepared from t-octylphenol and formaldehyde by a modified Zinke-Ziegler procedure; for many years, it was believed to be a cyclic tetrameric compound (3). Although the antibacterial mechanism of action of HOC compounds is not known, we have excluded extracellular inhibition of mycobacterial growth by Macrocyclon treatment (3,7,8). Therefore, it is believed that they work through a host-mediated mechanism (7), a view supported by reports showing activity in a wide range of in vivo models of infection in addition to tuberculosis (10).…”

mentioning

confidence: 99%

“…Calixarenes have been used as building blocks for host molecules with numerous applications in supramolecular chemistry (5); some were identified as having antimycobacterial activity (3,7). Most experimental work has been carried out with the compound Macrocyclon, also known as HOC 12.5EO, which was prepared by reacting the macrocycle HOC under basic conditions with ethylene oxide to give a heterogeneous compound with an average polyethylene glycol (PEG) chain of 12.5 U (3).…”

mentioning

confidence: 99%

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Antimycobacterial Calixarenes Enhance Innate Defense Mechanisms in Murine Macrophages and Induce Control ofMycobacterium tuberculosisInfection in Mice

et al. 2004

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Tuberculosis remains the leading cause of death among infectious diseases, accounting for more than two million deaths annually. The incidence of the disease is increasing globally, partially because of the resurgence of drug-resistant strains of Mycobacterium tuberculosis. Calixarenes are macrocyclic oligomers, some of which are able to modify the growth of M. tuberculosis in infected cells. Most experimental work has been carried out with Macrocyclon, also known as HOC 12.5EO. In this study, we demonstrate that Macrocyclon is effective in controlling M. tuberculosis infections, and we provide evidence that its effect is partially mediated by an L-arginine-dependent mechanism of macrophage activation that involves the activity of the inducible nitric oxide synthase. We also show that Macrocyclon is effective in athymic and major histocompatibility complex class II ؊/؊ mice and synthesized a number of structurally related calixarenes expressing significant antimycobacterial activity.Mycobacterium tuberculosis infects one-third of the world's population, and it accounts for more deaths each year than any other infectious bacterium (13). The problem, associated with multiple-drug resistance (12), has prompted a great interest in understanding new alternatives in host-mediated mechanisms of disease intervention. A new therapeutic agent, with activity mediated through a host-derived effector mechanism, would be particularly attractive, since it could be less susceptible to selection for drug resistance; if the balance between the pathogenic mycobacteria and the macrophage can be manipulated in favor of the host macrophage, it may be possible to develop novel adjunctive therapies for tuberculosis control.Calixarenes have been used as building blocks for host molecules with numerous applications in supramolecular chemistry (5); some were identified as having antimycobacterial activity (3, 7). Most experimental work has been carried out with the compound Macrocyclon, also known as HOC 12.5EO, which was prepared by reacting the macrocycle HOC under basic conditions with ethylene oxide to give a heterogeneous compound with an average polyethylene glycol (PEG) chain of 12.5 U (3). The compound HOC was prepared from t-octylphenol and formaldehyde by a modified Zinke-Ziegler procedure; for many years, it was believed to be a cyclic tetrameric compound (3). Although the antibacterial mechanism of action of HOC compounds is not known, we have excluded extracellular inhibition of mycobacterial growth by Macrocyclon treatment (3,7,8). Therefore, it is believed that they work through a host-mediated mechanism (7), a view supported by reports showing activity in a wide range of in vivo models of infection in addition to tuberculosis (10). In this study, we have extended observations on the parent preparation, Macrocyclon, to show that it significantly affects mycobacterial growth in murine macrophages by a mechanism requiring inducible nitric oxide synthase (iNOS) activity. In addition, we show that Macrocyclon is effective in at...

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antimycobacterial Calixarenes Enhance Innate Defense Mechanisms in Murine Macrophages and Induce Control ofMycobacterium tuberculosisInfection in Mice

et al. 2004

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“…P331 has successfully been used to treat toxoplasmosis in mice (19). Cornforth and Hart (4), Hart (9), Kondo and Kanai (18), and others demonstrated that surfactants with physicochemical properties similar to those of P331 produced a synergistic effect with antibiotics in vivo and increased the survival of mice following challenge with virulent M. tuberculosis, even though they had no effect on the growth of organisms in vitro (4,9,18). Since completion of the studies described here, additional experiments have been completed on the effects of poloxamer surfactants on M. tuberculosis in broth and macrophage cultures and on acute infections in mice (17a).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of antibiotic susceptibility and suppression of Mycobacterium avium complex growth by poloxamer 331

Hunter

Jagannath

Tinkley

et al. 1995

Antimicrob Agents Chemother

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The resistance of Mycobacterium avium complex (MAC) to antibiotics is thought to be enhanced by its outer glycolipid layer, which protects the organisms from antibiotics and host defense mechanisms. We hypothesized that surfactants which disrupt the lipid barrier might be of therapeutic value. We evaluated the ability of 10 poloxamer surfactants to inhibit the growth of MAC organisms and to potentiate antimycobacterial drug activity in broth culture using a radiometric assay. Very large, small, or hydrophilic poloxamers had little or no effect. However, certain hydrophobic poloxamers, especially P331, retarded the growth of most isolates of MAC and produced a synergistic effect with rifampin. The MIC of rifampin required to inhibit the growth of MAC was reduced from a mean of 14.6 g/ml (range, 4 to >32 g/ml) to 1.4 g/ml (range, <1.125 to 4 g/ml) by 1.0 mg of P331 per ml (P < 0.01). Enhancement of antibiotic susceptibility was observed with concentrations of poloxamer as low as 10 g/ml. These studies suggest that P331 might be useful in increasing the effectiveness of antibiotic therapy of MAC infections.

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“…The members of the Mycobacterium tuberculosis complex (16, 21), the causative agent of tuberculosis, and several other pathogenic mycobacteria, including M. marinum (7,15,32), have the ability to infect macrophages and survive within phagocytic cells (2,3,17). Despite several advances in the field in the wake of the availability of M. tuberculosis genomic information, much remains to be learned about the biology and pathogenesis of the tubercle bacillus.…”

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confidence: 99%

Molecular and Physiological Effects of Mycobacterial oxyR Inactivation

Pagán-Ramos

Master²,

Pritchett

et al. 2006

J Bacteriol

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The majority of slow-growing mycobacteria have a functional oxyR, the central regulator of the bacterial oxidative stress response. In contrast, this gene has been inactivated during the evolution of Mycobacterium tuberculosis. Here we inactivated the oxyR gene in Mycobacterium marinum, an organism used to model M. tuberculosis pathogenesis. Inactivation of oxyR abrogated induction of ahpC, a gene encoding alkylhydroperoxide reductase, normally activated upon peroxide challenge. The absence of oxyR also resulted in increased sensitivity to the front-line antituberculosis drug isoniazid. Inactivation of oxyR in M. marinum did not affect either virulence in a fish infection model or survival in human macrophages. Our findings demonstrate, at the genetic and molecular levels, a direct role for OxyR in ahpC regulation in response to oxidative stress. Our study also indicates that oxyR is not critical for virulence in M. marinum. However, oxyR inactivation confers increased sensitivity to isonicotinic acid hydrazide, suggesting that the natural loss of oxyR in the tubercle bacillus contributes to the unusually high sensitivity of M. tuberculosis to isoniazid.Tuberculosis is the number one cause of death from a single infectious agent in the world, with 8 million new cases of active disease each year, 2 million fatalities annually, and over a billion people latently infected (WHO fact sheet; http://www .who.int/mediacentre/factsheets/fs104/en/). The members of the Mycobacterium tuberculosis complex (16, 21), the causative agent of tuberculosis, and several other pathogenic mycobacteria, including M. marinum (7,15,32), have the ability to infect macrophages and survive within phagocytic cells (2,3,17). Despite several advances in the field in the wake of the availability of M. tuberculosis genomic information, much remains to be learned about the biology and pathogenesis of the tubercle bacillus. Evolutionarily, M. marinum is closely related to M. tuberculosis (38), causing tuberculosis like-disease in poikilothermic hosts, such as fish (6,26). In humans, M. marinum can cause localized disease that is restricted to the extremities (39). Due to its close evolutionary link to M. tuberculosis and apparent parallels between the diseases caused by the two microbes, M. marinum has been used effectively to study mycobacterial pathogenesis (1,14, 24,25,32,34).Recent studies of the oxidative stress response genes in mycobacteria have revealed that the two most significant mycobacterial pathogens, M. tuberculosis and M. leprae, paradoxically lack parts of their oxidative stress response defenses (11, 24). In M. tuberculosis, oxyR, the central regulator of bacterial oxidative and nitrosative stress response (18, 33), is surprisingly inactive (10,11,28); it is represented in the M. tuberculosis genome as an unannotated pseudogene (see Fig. 1A), located between the Rv2427c and Rv2428 (AhpC) open reading frames. M. leprae, on the other hand, has an intact oxyR but lacks a functional furA, the negative regulator of KatG (43). Despit...

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Mycobacterium tuberculosis in Macrophages: Effect of Certain Surfactants and Other Membrane-Active Compounds

Cited by 47 publications

References 19 publications

Antimycobacterial Calixarenes Enhance Innate Defense Mechanisms in Murine Macrophages and Induce Control ofMycobacterium tuberculosisInfection in Mice

Antimycobacterial Calixarenes Enhance Innate Defense Mechanisms in Murine Macrophages and Induce Control ofMycobacterium tuberculosisInfection in Mice

Enhancement of antibiotic susceptibility and suppression of Mycobacterium avium complex growth by poloxamer 331

Molecular and Physiological Effects of Mycobacterial oxyR Inactivation

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