ABSTRACT
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
ABSTRACT
Tuberculosis (TB) is a global disease causing 1.8 million deaths each year. The appearance of drug-resistant strains raised the demand for new anti-mycobacterial drugs and therapies, because previously discovered antibiotics are shown to be inefficient. Moreover, the number of newly discovered drugs is not increasing in proportion to the emergence of drug resistance, which suggests that more optimized methodology and screening procedures are required including the incorporation of in vivo properties of TB infection. A way to improve efficacy of screening approaches is by introducing the use of different host-pathogen systems into primary screenings. These include whole cell-based screenings, zebrafish larvae-based screenings and the impact of artificial granuloma research on the drug discovery process. This review highlights current screening attempts and the identified molecular targets and summarizes findings of alternative, not fully explored host-pathogen systems for the characterization of anti-mycobacterial compounds.
Subject(s)
Antitubercular Agents , Drug Discovery/methods , Models, Biological , Mycobacterium tuberculosis/drug effects , Tuberculosis , Animals , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Cell Line , Host-Pathogen Interactions , Humans , Mice , Tuberculosis/drug therapy , Tuberculosis/microbiologyABSTRACT
Tuberculosis (TB) is a leading infectious cause of death worldwide. The use of ethionamide (ETH), a main second line anti-TB drug, is hampered by its severe side effects. Recently discovered "booster" molecules strongly increase the ETH efficacy, opening new perspectives to improve the current clinical outcome of drug-resistant TB. To investigate the simultaneous delivery of ETH and its booster BDM41906 in the lungs, we co-encapsulated these compounds in biodegradable polymeric nanoparticles (NPs), overcoming the bottlenecks inherent to the strong tendency of ETH to crystallize and the limited water solubility of this Booster. The efficacy of the designed formulations was evaluated in TB infected macrophages using an automated confocal high-content screening platform, showing that the drugs maintained their activity after incorporation in NPs. Among tested formulations, "green" ß-cyclodextrin (pCD) based NPs displayed the best physico-chemical characteristics and were selected for in vivo studies. The NPs suspension, administered directly into mouse lungs using a Microsprayer®, was proved to be well-tolerated and led to a 3-log decrease of the pulmonary mycobacterial load after 6 administrations as compared to untreated mice. This study paves the way for a future use of pCD NPs for the pulmonary delivery of the [ETH:Booster] pair in TB chemotherapy.
Subject(s)
Antitubercular Agents/pharmacology , Drug Therapy, Combination/methods , Ethionamide/pharmacology , Mycobacterium tuberculosis/drug effects , Oxadiazoles/pharmacology , Piperidines/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Pulmonary/drug therapy , Administration, Inhalation , Animals , Disease Models, Animal , Drug Carriers , Drug Compounding/methods , Drug Synergism , Female , Humans , Mice , Mice, Inbred BALB C , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/pathogenicity , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , RAW 264.7 Cells , Solubility , Treatment Outcome , Tuberculosis, Multidrug-Resistant/microbiology , Tuberculosis, Multidrug-Resistant/pathology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology , beta-Cyclodextrins/chemistryABSTRACT
AIM: First extensive reformulation of clofazimine (CLZ) in nanoporous silica particles (NSPs) for tackling antibiotic-resistant tuberculosis (TB) infections. MATERIALS & METHODS: Solid-state characterization of several CLZ-encapsulated NSP formulations was followed by in vitro drug solubility, Caco-2 intestinal cells drug permeability and TB antibacterial activity. RESULTS: NSPs stabilize the amorphous state of CLZ (shelf stability >6 months) and dramatically increase the drug solubility in simulated gastric fluid (up to 20-fold) with different dissolution kinetics depending on the NSPs used. CLZ encapsulation in NSP substantially enhances the permeation through model intestinal cell layer, achieving effective antimicrobial concentrations in TB-infected macrophages. CONCLUSION: Promising results toward refurbishment of an approved marketed drug for a different indication suitable for oral anti-TB formulation.
Subject(s)
Clofazimine/administration & dosage , Mycobacterium tuberculosis/drug effects , Nanoparticles/administration & dosage , Tuberculosis/drug therapy , Administration, Oral , Caco-2 Cells , Clofazimine/chemistry , Drug Resistance, Bacterial/drug effects , Humans , Mycobacterium tuberculosis/pathogenicity , Nanoparticles/chemistry , Nanopores , Permeability/drug effects , Silicon Dioxide/administration & dosage , Silicon Dioxide/chemistry , Tuberculosis/microbiologyABSTRACT
Therapeutic approaches using nanoparticles are being successfully used in foods and in several fields of medicine, including infectious diseases. Regarding tuberculosis (TB) treatment, nanoparticles can be a useful strategy for two distinct applications: (i) for their intrinsic antimycobacterial activity; (ii) as vehicles for known antitubercular drugs to allow reduction of dose- and drug-associated side-effects and administration via user-friendly administration routes such as pulmonary or oral ones. Promising results were obtained in vitro and in animal Mycobacterium tuberculosis models and need now to be translated into clinical drug candidates. Such a prospect can provide an opportunity regarding the current limited therapeutic options for drug-resistant TB and the scarcity of novel antituberculosis drugs in the drug discovery pipeline.
