Abstract:Treatment of individuals coinfected with human immunodeficiency virus (HIV) type 1 and Mycobacterium tuberculosis is challenging due to the prolonged treatment requirements, drug toxicity, and emergence of drug resistance. Mononuclear phagocytes (MP; macrophages) are one of the natural reservoirs for both HIV and M. tuberculosis. Here, the treatment of HIV and M. tuberculosis coinfection was studied by preloading human macrophages with MP-targeted gallium (Ga) nanoparticles to limit subsequent simultaneous inf… Show more
“…44 GaNP is known to facilitate phagosome maturation, inhibit growth of M.tb in macrophages, inhibit HIV infection through release of interferons and can be targeted to human macrophages infected with both M.tb and HIV. 45,46 These studies support our results and point to the possibility that GaNP would be an effective intervention against bacterial biofilms. It has not escaped our attention that cyclosporine-A as an adjunct to existing anti-tubercular drugs could be a potential strategy to address the problem of eradicating latent TB by first activating the bacterium, by virtue of its immune-suppressive action, followed by the biofilm inhibition reported in our study.Fig.…”
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (M.tb), takes one human life every 15 s globally. Disease relapse occurs due to incomplete clearance of the pathogen and reactivation of the antibiotic tolerant bacilli. M.tb, like other bacterial pathogens, creates an ecosystem of biofilm formed by several proteins including the cyclophilins. We show that the M.tb cyclophilin peptidyl-prolyl isomerase (PpiB), an essential gene, is involved in biofilm formation and tolerance to anti-mycobacterial drugs. We predicted interaction between PpiB and US FDA approved drugs (cyclosporine-A and acarbose) by in-silico docking studies and this was confirmed by surface plasmon resonance (SPR) spectroscopy. While all these drugs inhibited growth of Mycobacterium smegmatis (M.smegmatis) when cultured in vitro, acarbose and cyclosporine-A showed bacteriostatic effect while gallium nanoparticle (GaNP) exhibited bactericidal effect. Cyclosporine-A and GaNP additionally disrupted M.tb H37Rv biofilm formation. Co-culturing M.tb in their presence resulted in significant (2–4 fold) decrease in dosage of anti-tubercular drugs- isoniazid and ethambutol. Comparison of the cyclosporine-A and acarbose binding sites in PpiB homologues of other biofilm forming infectious pathogens revealed that these have largely remained unaltered across bacterial species. Targeting bacterial biofilms could be a generic strategy for intervention against bacterial pathogens.
“…44 GaNP is known to facilitate phagosome maturation, inhibit growth of M.tb in macrophages, inhibit HIV infection through release of interferons and can be targeted to human macrophages infected with both M.tb and HIV. 45,46 These studies support our results and point to the possibility that GaNP would be an effective intervention against bacterial biofilms. It has not escaped our attention that cyclosporine-A as an adjunct to existing anti-tubercular drugs could be a potential strategy to address the problem of eradicating latent TB by first activating the bacterium, by virtue of its immune-suppressive action, followed by the biofilm inhibition reported in our study.Fig.…”
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (M.tb), takes one human life every 15 s globally. Disease relapse occurs due to incomplete clearance of the pathogen and reactivation of the antibiotic tolerant bacilli. M.tb, like other bacterial pathogens, creates an ecosystem of biofilm formed by several proteins including the cyclophilins. We show that the M.tb cyclophilin peptidyl-prolyl isomerase (PpiB), an essential gene, is involved in biofilm formation and tolerance to anti-mycobacterial drugs. We predicted interaction between PpiB and US FDA approved drugs (cyclosporine-A and acarbose) by in-silico docking studies and this was confirmed by surface plasmon resonance (SPR) spectroscopy. While all these drugs inhibited growth of Mycobacterium smegmatis (M.smegmatis) when cultured in vitro, acarbose and cyclosporine-A showed bacteriostatic effect while gallium nanoparticle (GaNP) exhibited bactericidal effect. Cyclosporine-A and GaNP additionally disrupted M.tb H37Rv biofilm formation. Co-culturing M.tb in their presence resulted in significant (2–4 fold) decrease in dosage of anti-tubercular drugs- isoniazid and ethambutol. Comparison of the cyclosporine-A and acarbose binding sites in PpiB homologues of other biofilm forming infectious pathogens revealed that these have largely remained unaltered across bacterial species. Targeting bacterial biofilms could be a generic strategy for intervention against bacterial pathogens.
“…Our previous works demonstrated that macrophage-targeted Ga(III) nanoparticles have a prolonged antimicrobial effect against Mycobacterium abscessus, Mycobacterium avium, Mycobacterium tuberculosis, and Mycobacterium smegmatis within macrophages because of sustained Ga(III) release over time (27)(28)(29)39). In the current work, we found that THP-1 cells preloaded with GaMP, CDGaPP, or eFGaMP exhibited resistance to P. aeruginosa infection, but only for 3 days, losing all activity at day 5 postloading.…”
Iron/heme acquisition systems are critical for microorganisms to acquire iron from the human host, where iron sources are limited due to the nutritional immune system and insolubility of the ferric form of iron. Prior work has shown that a variety of gallium compounds can interfere with bacterial iron acquisition. This study explored the intra-and extracellular antimicrobial activities of gallium protoporphyrin (GaPP), gallium mesoporphyrin (GaMP), and nanoparticles encapsulating GaPP or GaMP against the Gram-negative pathogens Pseudomonas aeruginosa and Acinetobacter baumannii, including clinical isolates. All P. aeruginosa and A. baumannii isolates were susceptible to GaPP and GaMP, with MICs ranging from 0.5 to ϳ32 g/ml in iron-depleted medium. Significant intra-and extracellular growth inhibition was observed against P. aeruginosa cultured in macrophages at a gallium concentration of 3.3 g/ml (5 M) of all Ga(III) compounds, including nanoparticles. Nanoparticle formulations showed prolonged activity against both P. aeruginosa and A. baumannii in previously infected macrophages. When the macrophages were loaded with the nanoparticles 3 days prior to infection, there was a 5-fold decrease in growth of P. aeruginosa in the presence of single emulsion F127 copolymer nanoparticles encapsulating GaMP (eFGaMP). In addition, all Ga(III) porphyrins and nanoparticles showed significant intracellular and antibiofilm activity against both pathogens, with the nanoparticles exhibiting intracellular activity for 3 days. Ga nanoparticles also increased the survival rate of Caenorhabditis elegans nematodes infected by P. aeruginosa and A. baumannii. Our results demonstrate that Ga nanoparticles have prolonged in vitro and in vivo activities against both P. aeruginosa and A. baumannii, including disruption of their biofilms.
“…The glyoxalase pathway is a promising drug target for neurodegenerative diseases. Drug discovery [4] , [140] , [141] , [142] , [143] , [144] and delivery [145] , [146] , [147] processes could be explored in this target against neurodegenerative diseases. Novel flavonoids could be designed, synthesized, and tested to protect neurodegenerative diseases through glyoxalase pathway.…”
The glyoxalase pathway functions to detoxify reactive dicarbonyl compounds, most importantly methylglyoxal. The glyoxalase pathway is an antioxidant defense mechanism that is essential for neuroprotection. Excessive concentrations of methylglyoxal have deleterious effects on cells, leading to increased levels of inflammation and oxidative stress. Neurodegenerative diseases – including Alzheimer's, Parkinson's, Aging and Autism Spectrum Disorder – are often induced or exacerbated by accumulation of methylglyoxal. Antioxidant compounds possess several distinct mechanisms that enhance the glyoxalase pathway and function as neuroprotectants. Flavonoids are well-researched secondary plant metabolites that appear to be effective in reducing levels of oxidative stress and inflammation in neural cells. Novel flavonoids could be designed, synthesized and tested to protect against neurodegenerative diseases through regulating the glyoxalase pathway.
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