FtsZ inhibition and redox modulation with one chemical scaffold: Potential use of dihydroquinolines against mycobacteria.

The dual effect of FtsZ inhibition and oxidative stress by a group of 1,2-dihydroquinolines that culminate in bactericidal effect on mycobacterium strains is demonstrated. They inhibited the non-pathogenic Mycobacterium smegmatis mc(2) 155 with MIC as low as 0.9 µg/mL and induced filamentation. Detailed studies revealed their ability to inhibit polymerization and GTPase activity of MtbFtsZ (Mycobacterial filamentous temperature sensitive Z) with an IC50 value of ∼40 µM. In addition to such target specific effects, these compounds exerted a global cellular effect by causing redox-imbalance that was evident from overproduction of ROS in treated cells. Such multi-targeting effect with one chemical scaffold has considerable significance in this era of emerging drug resistance and could offer promise in the development of new therapeutic agents against tuberculosis.

Phytochemicals as inhibitors of bacterial cell division protein FtsZ: coumarins are promising candidates.

Naturally occurring phytochemicals with reported antibacterial activity were screened for their ability to inhibit the bacterial cell division protein Escherichia coli FtsZ. Among the representative compounds, coumarins inhibit the GTPase and polymerization activities of this protein effectively. Further screening with ten coumarin analogs we identified two promising candidates, scopoletin and daphnetin. The former is found to inhibit the GTPase activity of the protein in a noncompetitive manner. Docking of these coumarins with the modeled protein indicate that they bind to T7 loop, which is different from the GTP-binding site (active site), thereby supporting the experimental data. Lowest binding energy is obtained with scopoletin. 3D QSAR indicates the need for groups such as hydroxyl, diethyl, or dimethyl amino in the 7th carbon for enhanced activity. None of the coumarins exhibited cytotoxicity against NIH/3T3 and human embryonic kidney cell lines. The length of Bacillus subtilis increases in the presence of these compounds probably due to the lack of septum formation. Results of this study indicate the role of coumarins in halting the first step of bacterial cell division process.

Serum levels of neopterin during antimicrobial treatment for Mycobacterium ulcerans infection.

Neopterin is closely associated with activation of the cellular immune system. Neopterin levels differed between controls and patients with Buruli ulcer disease. No differences between patients with or without paradoxical responses were observed. Therefore, neopterin has no value in detecting paradoxical responses among patients with limited Buruli ulcer disease. Neopterin levels were lower in patients receiving clarithromycin. This finding might indicate a slower cellular immune recovery, with possible consequences in future therapy with clarithromycin.

Immunology in tuberculosis: challenges in monitoring of disease activity and identifying correlates of protection.

Humans have always lived with tubercle bacilli. Host susceptibility both inherited and acquired determines whether an individual infected with Mycobacterium tuberculosis will eventually fall ill and develop tuberculosis (TB). After infection with M. tuberculosis, a latent TB infection may ensue reflected by immune recognition of specific antigenic epitopes expressed by M. tuberculosis the Region of Difference 1 proteins ESAT-6 and CFP-10 leading to interferon gamma release in vitro. Multi-Drug-Resistant TB has emerged as an enormous infectious threat in certain regions in the world, and the Acquired immunodeficiency by co-infection with HIV has accelerated the TB epidemic even further. A paradoxical response or Immune Response Inflammatory Syndrome in the context of treatment of HIV co-infection - is an increased inflammatory reaction during effective reduction in the bacterial load. This should be differentiated from treatment failure. A huge challenge is to develop novel markers that can differentiate paradoxical responses from treatment failure. We discuss the role of protection of vaccines especially BCG, iron metabolism and the role of vitamin D.

Identification and characterization of a major cell wall-associated iron-regulated envelope protein (Irep-28) in Mycobacterium tuberculosis.

Iron limitation and the expression of mycobactin and carboxymycobactin by Mycobacterium tuberculosis are known. Here, we report how iron regulated the coordinate expression of these two siderophores and a 28-kDa cell wall-associated iron-regulated protein (Irep-28). Irep-28 is identified as the DNA-binding HU homologue HupB protein (hupB [Rv2986c]). Antibodies to this protein were detected in sera from tuberculosis patients. The location of the protein in the cell wall makes it a potential drug target.