silicon and Tuberculosis

Growing global demand for new molecules to treat tuberculosis has created an urgent need to develop novel strategies to combat the menace. BM212 related compounds were found to be potent anti-TB agents and they inhibit mycolic acid transporter, MmpL3, a known potent drug target from Mycobacterium tuberculosis. In order to enhance their inhibitory potency, several silicon analogues of diarylpyrroles related to BM212 were designed, synthesized, and evaluated for anti-tubercular activities. In Alamar blue assay, most of the silicon-incorporated compounds were found to be more potent than the parent compound (BM212), against Mycobacterium tuberculosis (MIC = 1.7 μM, H37Rv). Docking results from the crystal structure of MmpL3 and silicon analogues as pharmacophore model also strongly correlate with the biological assays and suggest that the incorporation of silicon in the inhibitor scaffold could enhance their potency by stabilizing the hydrophobic residues at the binding pocket. The best docking hit, compound 12 showed an MIC of 0.1 μM against H37Rv with an acceptable in vitro ADME profile and excellent selectivity index. Overall, the present study indicates that, the designed silicon analogues, especially compound 12 could be a good inhibitor for an intrinsically flexible drug-binding pocket of MmpL3 and has potential for further development as anti-tubercular agents.

Topics: Antitubercular Agents; Bacterial Proteins; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Silicon; Tuberculosis

Tuberculosis (TB) is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, based on the WHO Global Tuberculosis Report in 2017. TB causes massive health care burdens in many parts of the world, specifically in the resource constrained developing world. Most deaths from TB could be prevented with cost effective early diagnosis and appropriate treatment.. Conventional TB detection methods are either too slow as it takes a few weeks for diagnosis or they lack the specificity and accuracy. Thus the objective of this study was to develop a fast and efficient detection for TB using surface enhanced Raman scattering (SERS) technique.. SERS spectra for different forms of mycolic acids (MAs) that are both synthetic origin and actual extracts from the mycobacteria species were obtained by label-free direct detection mode. Similarly, we collected SERS spectra for γ-irradiated whole bacteria (WB). Measurements were done using silver (Ag) coated silicon nanopillar (Ag SNP) as SERS substrate.. We report the SERS based detection of MA, which is a biomarker for mycobacteria species including. We have demonstrated the direct detection of three major forms of MA - αMA, methoxy-MA, and keto-MA, in two different types of MA extracts from MTB bacteria, namely delipidated MA and undelipidated MA and finally in γ-irradiated WB. In the near future, this study could pave the way for a fast and efficient detection method for TB, which is of high clinical significance.

Topics: Chromatography, Liquid; Humans; Mass Spectrometry; Mycobacterium tuberculosis; Mycolic Acids; Nanoparticles; Silicon; Silver; Spectrum Analysis, Raman; Tuberculosis

Worldwide, tuberculosis (TB) remains one of the most prevalent infectious diseases causing morbidity and death in >1.5 million patients annually. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, usually resides in the alveolar macrophages. Current tuberculosis treatment methods require more than six months, and low compliance often leads to therapeutic failure and multidrug resistant strain development. Critical to improving TB-therapy is shortening treatment duration and increasing therapeutic efficacy. In this study, we sought to determine if lung hemodynamics and pathological changes in Mtb infected cells can be used for the selective targeting of microparticles to infected tissue(s). Thioaptamers (TA) with CD44 (CD44TA) targeting moiety were conjugated to discoidal silicon mesoporous microparticles (SMP) to enhance accumulation of these agents/carriers in the infected macrophages in the lungs. In vitro, CD44TA-SMP accumulated in macrophages infected with mycobacteria efficiently killing the infected cells and decreasing survival of mycobacteria. In vivo, increased accumulations of CD44TA-SMP were recorded in the lung of M. tuberculosis infected mice as compared to controls. TA-targeted carriers significantly diminished bacterial load in the lungs and caused recruitment of T lymphocytes. Proposed mechanism of action of the designed vector accounts for a combination of increased uptake of particles that leads to infected macrophage death, as well as, activation of cellular immunity by the TA, causing increased T-cell accumulation in the treated lungs. Based on our data with CD44TA-SMP, we anticipate that this drug carrier can open new avenues in TB management.

Topics: Animals; Aptamers, Nucleotide; Cells, Cultured; Drug Carriers; Female; Humans; Hyaluronan Receptors; Lung; Macrophages; Mice, Inbred BALB C; Mycobacterium tuberculosis; Silicon; T-Lymphocytes; Tuberculosis

A nanometer silicon membrane sandwich cup system was self-designed. It could concentrate the bacilli via 0.45-μm microporous filter membrane and semi-automate the acid-fast bacilli (AFB) by a bacteria-staining machine. The aim of the study was to assess the clinical value of our self-designed system for diagnosing tuberculosis (TB).. A total of 1993 sputum specimens obtained from patients with confirmed or suspected TB were subjected to direct or concentrated specimens smear at XiangYa Hospital, Central South University between May 2012 and February 2013. In addition, all the specimens were also inoculated into Lowenstein-Jensen (L-J) media, and culture results were considered as the gold standard for calculating sensitivity and specificity.. Compared with direct smear examination, an increased density of red stained bacilli was observed in the self-designed nanometer silicon membrane sandwich cup analysis under the microscope. The positive rate of the self-designed analysis was significantly higher than that of direct AFB smear [10.9% (217/1993) vs 6.2% (123/1993), P < 0.05]. The sensitivity of the self-designed system increased (97.3% vs 55.2%, P < 0.05) without a loss of specificity (100% vs 100%) for identifying positive TB cases compared with the direct smear method.. The self-designed nanometer silicon membrane sandwich cup and semi-automatic bacteria-staining machine could more efficiently and rapidly detect the AFB in respiratory specimens than direct microscopy. This is a novel and safe examination, and it may replace direct smear examination for the diagnosis of patients with TB.

Topics: Bacteriological Techniques; Female; Humans; Male; Microscopy; Mycobacterium tuberculosis; Predictive Value of Tests; Sensitivity and Specificity; Silicon; Sputum; Tuberculosis

Global tuberculosis (TB) control is hampered by cost and slow or insensitive diagnostic methods to be used for TB diagnosis in clinic. Thus, TB still remains a major global health problem. The failure to rapidly and accurately diagnose of TB has posed significant challenges with consequent secondary resistance and ongoing transmission. We developed a rapid Mycobacterium tuberculosis (MTB) amplification/detection method, called MTB isothermal solid-phase amplification/detection (MTB-ISAD), that couples isothermal solid-phase amplification and a silicon biophotonics-based detection sensor to allow the simultaneous amplification and detection of MTB in a label-free and real-time manner. We validated the clinical utility of the MTB-ISAD assay by detecting MTB nucleic acid in sputum samples from 42 patients. We showed the ability of the MTB-ISAD assay to detect MTB in 42 clinical specimens, confirming that the MTB-ISAD assay is fast (<20 min), highly sensitive, accurate (>90%, 38/42), and cost-effective because it is a label-free method and does not involve thermal cycling. The MTB-ISAD assay has improved time-efficiency, affordability, and sensitivity compared with many existing methods. Therefore, it is potentially adaptable for better diagnosis across various clinical applications.

Topics: Biosensing Techniques; DNA, Bacterial; Equipment Design; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Sensitivity and Specificity; Silicon; Sputum; Tuberculosis

Topics: Abscess; Bacterial Typing Techniques; Behavior; Brazil; Buttocks; Cluster Analysis; Humans; Molecular Typing; Muscular Diseases; Mycobacterium tuberculosis; Silicon; Surgery, Plastic; Transvestism; Tuberculosis

An experimental mouse model of normal and deficient content of silicon in the diet in CBA strain has been developed. It is shown that after BCG vaccination silicon deficiency brought about a dramatic decrease of in vitro proliferation of splenic lymphocytes in the presence of mycobacterial antigens, ConA or in the absence of the stimuli. DTH response to tuberculin in silicon deficient mice was also reduced. The level of specific serum IgG did not depend upon silicon content in the diet. The addition of silicon into the diet of silicon-deficient mice beginning from BCG vaccination restored the level of immune reactions.

Topics: Animal Feed; Animals; Antigens, Bacterial; BCG Vaccine; Concanavalin A; In Vitro Techniques; Lymphocytes; Mice; Mice, Inbred CBA; Mycobacterium tuberculosis; Silicon; Tuberculin; Tuberculosis

Topics: Hematologic Tests; Humans; Oxalates; Oxalic Acid; Silicon; Tuberculosis; Tuberculosis, Pulmonary