thiourea and Tuberculosis

The genome of the human intracellular pathogen

Topics: Adamantane; Epoxide Hydrolases; Gene Expression Regulation, Bacterial; Humans; Mycobacterium tuberculosis; Phenylurea Compounds; Thioacetazone; Thiourea; Tuberculosis; Urea

Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We have previously shown that 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits HIV replication in human macrophages through the induction of autophagy. In this study, we report that physiological concentrations of 1,25D3 induce the production of the human cathelicidin microbial peptide (CAMP) and autophagic flux in HIV and M. tuberculosis co-infected human macrophages which inhibits mycobacterial growth and the replication of HIV. Using RNA interference for Beclin-1 and the autophagy-related 5 homologue, combined with the chemical inhibitors of autophagic flux, bafilomycin A₁, an inhibitor of autophagosome-lysosome fusion and subsequent acidification, and SID 26681509 an inhibitor of the lysosome hydrolase cathepsin L, we show that the 1,25D3-mediated inhibition of HIV replication and mycobacterial growth during single infection or dual infection is dependent not only upon the induction of autophagy, but also through phagosomal maturation. Moreover, through the use of RNA interference for CAMP, we demonstrate that cathelicidin is essential for the 1,25D3 induced autophagic flux and inhibition of HIV replication and mycobacterial growth. The present findings provide a biological explanation for the benefits and importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections.

Topics: Antimicrobial Cationic Peptides; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Beclin-1; Calcifediol; Cathelicidins; Cells, Cultured; HIV Infections; HIV-1; Humans; Hydrazines; Macrolides; Macrophages; Membrane Proteins; Microtubule-Associated Proteins; Mycobacterium tuberculosis; Phagosomes; RNA Interference; RNA, Small Interfering; Thiourea; Tuberculosis

During Mycobacterium tuberculosis infection, a population of bacteria likely becomes refractory to antibiotic killing in the absence of genotypic resistance, making treatment challenging. We describe an in vitro model capable of yielding a phenotypically antibiotic-tolerant subpopulation of cells, often called persisters, within populations of Mycobacterium smegmatis and M. tuberculosis. We find that persisters are distinct from the larger antibiotic-susceptible population, as a small drop in dissolved oxygen (DO) saturation (20%) allows for their survival in the face of bactericidal antibiotics. In contrast, if high levels of DO are maintained, all cells succumb, sterilizing the culture. With increasing evidence that bactericidal antibiotics induce cell death through the production of reactive oxygen species (ROS), we hypothesized that the drop in DO decreases the concentration of ROS, thereby facilitating persister survival, and maintenance of high DO yields sufficient ROS to kill persisters. Consistent with this hypothesis, the hydroxyl-radical scavenger thiourea, when added to M. smegmatis cultures maintained at high DO levels, rescues the persister population. Conversely, the antibiotic clofazimine, which increases ROS via an NADH-dependent redox cycling pathway, successfully eradicates the persister population. Recent work suggests that environmentally induced antibiotic tolerance of bulk populations may result from enhanced antioxidant capabilities. We now show that the small persister subpopulation within a larger antibiotic-susceptible population also shows differential susceptibility to antibiotic-induced hydroxyl radicals. Furthermore, we show that stimulating ROS production can eradicate persisters, thus providing a potential strategy to managing persistent infections.

Topics: Anti-Bacterial Agents; Clofazimine; Drug Resistance, Bacterial; Green Fluorescent Proteins; In Vitro Techniques; Mycobacterium smegmatis; Mycobacterium tuberculosis; Oxygen; Reactive Oxygen Species; Thiourea; Tuberculosis

A new series of 20 quinoline derivatives possessing triazolo, ureido and thioureido substituents have been synthesized and their antimycobacterial properties have been evaluated. Compounds 10, 22 and 24 inhibited Mycobacterium tuberculosis H37Rv up to 96%, 98% and 94% respectively, at a fixed concentration of 6.25 microg/mL. Minimum inhibitory concentration of 3.125 microg/mL was obtained for compound 10 and 24, while for compound 22 it was 6.25 microg/mL. Molecular docking calculations suggest critical hydrogen bonding and electrostatic interactions between polar functional groups (such as quinoline-nitrogen, urea-carbonyl and hydroxyl) of anti-mycobacterial (anti-TB) compounds and amino acids (Arg186 and Glu61) of ATP-synthase of M. tuberculosis, could be the probable reason for observed anti-mycobacterial action.

Topics: Animals; Antitubercular Agents; ATP Synthetase Complexes; Bacterial Proteins; Cell Survival; Macrophages; Models, Molecular; Molecular Structure; Murinae; Mycobacterium tuberculosis; Protein Binding; Quinolines; Structure-Activity Relationship; Thiourea; Triazoles; Tuberculosis; Urea

The objective of this work was to synthesize 15 new 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(sub)phenyl/pyridylthiourea compounds and evaluate their in vitro and in vivo antimycobacterial activities.. 5-Cyclobutyloxazol-2-amine was reacted with 1,1'-thiocarbonyldiimidazole, followed by various substituted anilines and 2-amino pyridines to yield the 15 compounds, which were subjected to in vitro and in vivo evaluation against Mycobacterium tuberculosis H37Rv (MTB) and a clinical isolate of multidrug-resistant M. tuberculosis (MDR-TB).. Among the 15 compounds screened, 7 compounds inhibited both MTB and MDR-TB in vitro with MICs of < 1 microM. In the in vivo screening, compound 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(2'-trifluoromethyl)phenylthiourea (compound 8) was equally active as isoniazid at the same dose level.. Compound 8 was found to be the most active, with an in vitro MIC of 0.14 microM and was 2.5 and 80 times more active than isoniazid against MTB and MDR-TB, respectively. Compound 8 was non-toxic to Vero cells up to 183 microM, with a selectivity index of > 1307. In the in vivo animal model, compound 8 decreased the mycobacterium load in lung and spleen tissues with 2.8 and 3.94 log(10) reductions, respectively.

Topics: Animals; Antitubercular Agents; Cell Survival; Chlorocebus aethiops; Drug Resistance, Multiple, Bacterial; Female; Isoniazid; Magnetic Resonance Spectroscopy; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyridines; Structure-Activity Relationship; Tetrazolium Salts; Thiazoles; Thiourea; Tuberculosis; Vero Cells

Topics: Animals; Antitubercular Agents; Isoniazid; Mice; Streptomycin; Thiourea; Tuberculosis

Topics: Brazil; Humans; Leprosy; Phenylthiourea; Taste; Thiourea; Tuberculosis; White People

Topics: Drug Therapy; Isoniazid; Phenylthiourea; Thiourea; Toxicology; Tuberculosis; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Cycloserine; Oxytetracycline; Phenazines; Thiourea; Tuberculosis; Tuberculosis, Female Genital; Tuberculosis, Gastrointestinal; Tuberculosis, Hepatic; Tuberculosis, Pulmonary; Tuberculosis, Urogenital; Viomycin

Topics: Adolescent; Child; Diabetes Mellitus; Geriatrics; Italy; Neoplasms; Phenylthiourea; Research; Taste; Thiourea; Tuberculosis

Topics: Antitubercular Agents; Chemical Phenomena; Chemistry; Pharmacology; Phenylthiourea; Thiourea; Toxicology; Tuberculosis

Topics: Thiourea; Tuberculosis; Tuberculosis, Pulmonary

Topics: Phenylthiourea; Thiourea; Tuberculosis; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Isoniazid; Streptomycin; Thiourea; Tuberculosis; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Isoniazid; Thiourea; Tuberculosis; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Humans; In Vitro Techniques; Mycobacterium tuberculosis; Thiourea; Tuberculosis

Topics: Animals; Animals, Laboratory; Antitubercular Agents; In Vitro Techniques; Thiourea; Tuberculosis

Topics: Animals; Animals, Laboratory; Antitubercular Agents; Biphenyl Compounds; Thiourea; Tuberculosis

Topics: Chloroform; Disease; Humans; Liniments; Thiourea; Thoracic Diseases; Thorax; Tuberculosis; Tuberculosis, Pulmonary

Topics: Anti-Bacterial Agents; Thiouracil; Thiourea; Thyroid Gland; Tuberculosis; Tuberculosis, Pulmonary; Viscera

Topics: Animals; Mice; Mycobacterium tuberculosis; Thiourea; Tuberculosis

Topics: Animals; Guinea Pigs; Thiourea; Tuberculosis

Topics: Anti-Bacterial Agents; Thiourea; Tuberculosis

Topics: Analgesics; Humans; Thiourea; Tuberculosis; Tuberculosis, Pulmonary

Topics: Humans; Thiourea; Tuberculosis

Topics: Agranulocytosis; BCG Vaccine; Biological Phenomena; Physiological Phenomena; Propylthiouracil; Thiouracil; Thiourea; Tuberculosis

Topics: Accidents; Humans; Pleura; Sulfanilamide; Sulfanilamides; Sulfonamides; Thiourea; Tuberculosis; Tuberculosis, Pleural