This invention provides reagents and methods for specifically delivering antibiotic, antimicrobial and antiviral compounds, drugs and agents to phagocytic mammalian cells. The invention also relates to specific delivery to and uptake of such compounds by phagocytic cells. The invention specifically relates to reagents and methods for facilitating the entry of antibiotic, antimicrobial and antiviral compounds, drugs and agents into phagocytic cells. The invention specifically provides compositions of matter and pharmaceutical embodiments of such compositions comprising such antibiotic, antimicrobial or antiviral compounds, drugs and agents conjugated to, impregnated with or coated onto particulate carriers generally termed microparticles. In particular embodiments, the antibiotic, antimicrobial and antiviral compounds, drugs and agents are covalently linked to a microparticle via a specifically-degradable linker molecule which is the target of a microorganism-specific protein having enzymatic activity. Also provided are porous microparticles impregnated with antibiotic, antimicrobial or antiviral compounds, drugs and agents wherein the surface or outside extent of the microparticle is covered with a degradable coating that is specifically degraded within an infected phagocytic mammalian cell. Also provided are nonporous microparticles coated with antibiotic, antimicrobial or antiviral compounds, drugs and agents and further coated wherein the surface or outside extent of the microparticle is covered with a degradable coating that is specifically degraded within an infected phagocytic mammalian cell. Thus, the invention provides cell targeting of drugs wherein the targeted drug is only released in cells infected with a particular microorganism. Methods of inhibiting, attenuating, arresting, combating and overcoming microbial infection of phagocytic mammalian cells in vivo and in vitro, especially cells infected with tuberculosis-causing and other Mycobacterium species microorganisms, are also provided.

Covalent microparticle-drug conjugates for biological targeting

We demonstrated that products of the L-arginine-dependent pathway of human alveolar macrophages (AM) effectively kill the Mycobacterium bovis bacillus Calmette-Guerin (BCG) in vitro. The formation of products was triggered by inoculation with BCG itself. Many reports have shown that activated rodent AM could produce an amount of nitric oxide (NO) sufficient to suppress the growth of mycobacteria. However, there have been no definitive results as to whether human AM might have the NO-dependent mechanism for the killing of mycobacteria. Therefore, we have undertaken some experiments to answer this question. Immunofluorescence assays showed an increased production of inducible nitric oxide synthase (iNOS) and peroxynitrite in BCG-inoculated AM from patients with pulmonary fibrosis. Reverse transcriptase-PCR also revealed the higher expression of iNOS-coding mRNA. Colony assays demonstrated that these human AM effectively killed BCG in their cytoplasm. However, treatment of AM with N(G)-monomethyl-L-arginine monoacetate resulted in markedly reduced killing activity. These results clearly show that BCG-induced NO and its reactive product with the oxygen radical peroxynitrite could play an important role in the killing of BCG in human AM.

Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages.

Inducible nitric oxide synthase of macrophages. Present knowledge and evidence for species-specific regulation

The relative virulence and avirulence of Mycobacterium tuberculosis strains H37Rv and H37Ra were previously defined using animal infection models. To investigate host species' specificity of mycobacterial virulence, growth of the 2 M. tuberculosis strains in human monocyte-derived macrophages in vitro was studied. Mycobacterial growth was evaluated by acid-fast staining, electron microscopy, and colony-forming units (cfu) assay. As expected, the 2 strains demonstrated significantly different growth rates in mouse macrophages in vitro (53 h for H37Rv, 370 h for H37Ra). In marked contrast, in human macrophages the average division times of the strains were nearly equal (80 h for H37Rv and 76 h for H37Ra by cfu measurement, and 96 h for H37Rv and 104 h for H37Ra by acid-fast staining). These findings indicate that observations of mycobacterial virulence in murine systems may not necessarily translate to the human system, in which different mechanisms to control mycobacterial growth may be expressed.

Comparable Growth of Virulent and Avirulent Mycobacterium tuberculosis in Human Macrophages In Vitro

Previous work in our laboratory has shown that corticosterone increases the susceptibility of macrophages from Bcgs mice to the growth of Mycobacterium avium. The innate antimycobacterial activity of macrophages from Bcgr mice was not affected by corticosterone. In contrast to the differential effect of corticosterone on the antimycobacterial activity of the macrophages, corticosterone suppressed the production of tumor necrosis factor alpha and nitric oxide by macrophages from both Bcgr and Bcgs mice. The purpose of this investigation was to compare the effects of corticosterone on the antimycobacterial activity of macrophages from Bcgr and Bcgs mice that have been activated in vitro with recombinant gamma interferon or granulocyte-macrophage colony-stimulating factor. We found that macrophages from both strains of congenic mice responded equally to the activation stimuli. The capacity of the activated macrophages from Bcgs mice to suppress the growth of M. avium was inhibited by the addition of corticosterone to the cultures. The addition of NG-monomethyl-L-arginine to the cultures did not affect the capacity of resident splenic macrophages from Bcgr mice to limit the growth of M. avium. However, NG-monomethyl-L-arginine reduced the capacity of gamma interferon-activated, but not granulocyte-macrophage colony-stimulating factor-activated, macrophages to limit the growth of M. avium by macrophages from both Bcgr and Bcgs mice. The addition of corticosterone suppressed Nramp expression by macrophages from Bcgs mice. Nramp expression by macrophages from Bcgr mice was not affected by corticosterone.

Cytokine-mediated activation of macrophages from Mycobacterium bovis BCG-resistant and -susceptible mice: differential effects of corticosterone on antimycobacterial activity and expression of the Bcg gene (Candidate Nramp).

Mycobacteria preferentially reside in resident macrophages whereas activated macrophages are presumed to eliminate the bacteria effectively. The aim of the present study was to determine the antibacterial activities of resident and activated murine peritoneal macrophages against Mycobacterium fortuitum and the intracellular mechanisms involved. After phagocytosis M. fortuitum could not be killed by either BCG/PPD-activated and IFN-gamma-activated macrophages and resident macrophages. The mycobacteria did not multiply in BCG/PPD-activated macrophages and the rate of proliferation of M. fortuitum in IFN-gamma-activated macrophages was only slightly inhibited compared to that in resident macrophages. Experiments with selective inhibitors of the production of reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI) demonstrated that these factors are not essential for the mycobacteriostatic activity of BCG/PPD-activated macrophages. After phagocytosis of M. fortuitum, BCG/PPD-activated and IFN-gamma-activated macrophages produced substantial amounts of both RNI and ROI. No correlation was found between the levels of these intermediates and the proliferation of M. fortuitum in the macrophages. In conclusion, BCG/PPD-activated macrophages are bacteriostatic, but not bacteriocidal for M. fortuitum and the former does not involve reactive nitrogen and oxygen intermediates.

Bacteriostatic activity of BCG/PPD-activated macrophages against Mycobacterium fortuitum does not involve reactive nitrogen or oxygen intermediates.

Cell-mediated immunity against mycobacteria has been known for more than 100 years (1). This type of immunity is the result of cooperation between at least two types of cells: T lymphocytes and macrophages. The specificity of the immunity lies in the interaction between T cells and the mycobacterial antigens presented by macrophages and dendritic cells. CD4+ as well as CD8+ T cells produce a number of cytokines, e.g. IFN-γ, GM-CSF, IL-2, IL-4 and IL-6, which can activate macrophages and thus enhance their antimy-cobacterial functions (2–6). These activated macrophages are thought to be the ultimate effector cells of cellular immunity against mycobacteria. Other types of cell, such as CD8+ T cells (7), NK cells (8) and (activated) granulocytes (9), also play an important role in the defense against mycobacterial infections as well.

Interaction between activated macrophages and Mycobacterium fortuitum

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Bacteriostatic activity of BCG/PPD-activated macrophages against Mycobacterium fortuitum does not involve reactive nitrogen or oxygen intermediates.

Interaction between activated macrophages and Mycobacterium fortuitum