A Nanostructured Lipid System to Improve the Oral Bioavailability of Ruthenium(II) Complexes for the Treatment of Infections Caused by Mycobacterium tuberculosis

Tuberculosis (TB) is an infectious, airborne disease caused by the bacterium Mycobacterium tuberculosis that mainly affects the lungs. Fortunately, tuberculosis is a curable disease, and in recent years, death rates for this disease have decreased. However, the existence of antibiotic-resistant strains and the occurrence of co-infections with human immunodeficiency virus (HIV), have led to increased mortality in recent years. Another area of concern is that one-third of the world′s population is currently infected with M. tuberculosis in its latent state, serving as a potential reservoir for active TB. In an effort to address the failure of current TB drugs, greater attention is being given to the importance of bioinorganic chemistry as an ally in new research into the development of anti-TB drugs. Ruthenium (Ru) is a chemical element that can mimic iron (Fe) in the body. In previous studies involving the following heteroleptic Ru complexes, [Ru(pic)(dppb)(bipy)]PF6 (SCAR1), [Ru(pic)(dppb)(Me-bipy)]PF6 (SCAR2), [Ru(pic)(dppb)(phen)]PF6 (SCAR4), cis-[Ru(pic)(dppe)2]PF6 (SCAR5), and [Ru(pic)(dppe)(phen)]PF6 (SCAR7), we observed excellent anti-TB activity, moderate cell-toxicity, and a lack of oral bioavailability in an in vivo model of these complexes. Therefore, the objective of this study was to evaluate the toxicity and oral bioavailability of these complexes by loading them into a nanostructured lipid system. The nanostructured lipid system was generated using different ratios of surfactant (soybean phosphatidylcholine, Eumulgin®, and sodium oleate), aqueous phase (phosphate buffer with a concentration of 1X and pH 7.4), and oil (cholesterol) to generate a system for the incorporation of Ru(II) compounds. The anti-TB activity of the compounds was determined using a microdilution assay with Resazurin (REMA) against strains of M. tuberculosis H37Rv and clinical isolates resistant. Cytotoxicity assay using J774.A1 cells (ATCC TIB-67) and intra-macrophage activity were performed. The oral bioavailability assay was used to analyze blood collected from female BALB/C mice. Plasma collected from the same mice was analyzed via inductively coupled plasma mass spectrometry (ICP-MS) to quantify the number of Ru ions. The complexes loaded into the nanostructured lipid system maintained in vitro activity and toxicity was found to be reduced compared with the compounds that were not loaded. The complexes showed intra-macrophagic activity and were orally bioavailable

Latent Tuberculosis: A Promising New Compound to Treat Non-Replicating and Intramacrophagic Mycobacteria

As a biologic reservoir of Mycobacterium tuberculosis (M. tb), one-quarter of the world population is infected with the well-known latent tuberculosis (LTBI). About 5–10% of LTBI patients will progress to active disease in the first years after primary infection and, despite using the recommended treatment, 20% can still reactivate the infection. A new LTBI treatment could minimize adverse effects and antibiotic resistance that can occur when the same drug is used to treat the latent and active disease. New hydrazones were evaluated, and they showed great inhibitory activity against intramacrophagic and non-replicating M. tb, commonly found at this stage of infection, in addition to bactericidal and narrow-spectrum activity. When tested against eukaryotic cells, the hydrazones showed great safety at different exposure times. In vitro, these compounds performed better than isoniazid and could be considered new candidates for LTBI treatment, which may promote greater engagement in its prescription and adherence

Design, Synthesis, and Characterization of N‑Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity

Tuberculosis, caused by Mycobacterium tuberculosis (<i>Mtb</i>), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by <i>in vitro</i> and <i>in vivo</i> evaluation of their antitubercular potential against <i>Mtb</i>. Compound <b>8</b> was found to be the most promising compound, with MIC₉₀ values of 1.10 and 6.62 μM against active and nonreplicating <i>Mtb</i>, respectively. Additionally, we carried out <i>in vivo</i> experiments to confirm the safety and efficacy of compound <b>8</b>; the compound was found to be orally bioavailable and highly effective, leading to a reduction of <i>Mtb</i> to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound <b>8</b> blocks translation. Altogether, these results indicate that benzofuroxan derivative <b>8</b> is a promising lead compound for the development of a novel chemical class of antitubercular drugs