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Biomed Pharmacother ; 131: 110782, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33152940


Multidrug-resistant tuberculosis (MDR-TB) remains a serious public health threat worldwide. To date, the anti-TB activity of TB47 (T), an imidazopyridine amide class of antibiotics targeting QcrB in the electron transport chain, has not been systematically evaluated, especially in a new regimen against MDR-TB. This study employed both macrophage infection and a mouse model to test the activity of T alone or in combination with other antimicrobial agents. Different regimens containing amikacin (A), levofloxacin (L), ethambutol (E), and pyrazinamide (Z) + clofazimine (C)/T were evaluated in the mouse model. The bacterial burdens of mice from different groups were monitored at different time points while relapse was assessed 6 months after treatment cessation. Colonies obtained at relapse underwent drug susceptibility testing. We found that T exhibited highly synergistic bactericidal activity with C in all models. Adding T to ALEZC might shorten the MDR-TB treatment duration from ≥ 9 months to ≤ 5months, as five months of treatment with ALEZCT achieved zero relapse rates in 2 animal experiments. These findings indicate that T exhibits a highly synergistic sterilizing activity when combined with C. All isolates from relapsing mice remained sensitive to each drug, suggesting that the relapse was not due to drug resistance but rather associated with the type of regimen.

Nat Commun ; 10(1): 524, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705268


Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log10 CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU.

Antibacterianos/uso terapêutico , Úlcera de Buruli/tratamento farmacológico , Úlcera de Buruli/microbiologia , Mycobacterium ulcerans/efeitos dos fármacos , Mycobacterium ulcerans/patogenicidade , Animais , Complexo III da Cadeia de Transporte de Elétrons/genética , Camundongos , Mutação , Mycobacterium ulcerans/genética
Infect Drug Resist ; 11: 891-894, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29942141


Ethionamide (ETA) and prothionamide (PRO) are interchangeably used in tuberculosis (TB) chemotherapy regimens. Subtle discrepancies between biochemical and genetic information on the modes of sensitivity and resistance of isoniazid (INH) and ETA warrants further studies. We report a new mutation - EthAW21R - in Mycobacterium bovis Bacillus Calmette-Guérin that corresponds with co-resistance to both PRO and ETA, which to the best of our knowledge has not been reported before. Our findings suggest that mutation EthAW21R could be used as a marker site for testing PRO and ETA cross-resistance.

Biomed Pharmacother ; 94: 468-473, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28779708


Our research group previously isolated and identified a strain of pathogenic Escherichia coli from clinical samples called E. coli O124 K72. The present study was aimed at determining the potential effects of E. coli O124 K72 on intestinal barrier functions and structural proteins integrity in guinea pig. Guinea pigs were grouped into three groups; control (CG); E. coli O124 K72 (E. coli); and probiotics Lactobacillus rhamnosus (LGG). Initially, we create intestinal dysbiosis by giving all animals Levofloxacin for 10days, but the control group (CG) received the same volume of saline. Then, the animals received either E. coli O124 K72 (E. coli) or Lactobacillus rhamnosus (LGG) according to their assigned group. E. coli O124 K72 treatment significantly affected colon morphology and distorted intestinal barrier function by up-regulating Claudin2 and down-regulating Occludin. In addition, E. coli upregulated the mRNA expression of MUC1, MUC2, MUC13 and MUC15. Furthermore, suspected tumor was found in the E. coli treated animals. Our results suggested that E. coli O124 K72 strain has adverse effects on intestinal barrier functions and is capable of altering integrity of structural proteins in guinea pig model while at same time it may have a role in colon carcinogenesis.

Escherichia coli/fisiologia , Intestinos/microbiologia , Intestinos/patologia , Proteínas de Junções Íntimas/metabolismo , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Claudina-2/metabolismo , Eletroforese em Gel de Gradiente Desnaturante , Modelos Animais de Doenças , Disbiose/tratamento farmacológico , Disbiose/metabolismo , Disbiose/microbiologia , Disbiose/patologia , Microbioma Gastrointestinal , Cobaias , Intestinos/efeitos dos fármacos , Mucina-2/metabolismo , Ocludina/metabolismo
Dig Dis Sci ; 61(10): 2908-2920, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27384052


BACKGROUND: Structural change in the gut microbiota is implicated in cancer. The beneficial modulation of the microbiota composition with probiotics and prebiotics prevents diseases. AIM: We investigated the effect of oligofructose-maltodextrin-enriched Lactobacillus acidophilus, Bifidobacteria bifidum, and Bifidobacteria infantum (LBB), on the gut microbiota composition and progression of colorectal cancer. METHODS: Sprague Dawley rats were acclimatized, given ampicillin (75 mg/kg), and treated as follows; GCO: normal control; GPR: LBB only; GPC: LBB+ 1,2-dimethylhydrazine dihydrochloride (DMH); and GCA: DMH only (cancer control). 16S V4 Pyrosequencing for gut microbiota analysis, tumor studies, and the expression of MUC2, ZO-1, occludin, TLR2, TLR4, caspase 3, COX-2, and ß-catenin were conducted at the end of experiment. RESULTS: Probiotic LBB treatment altered the gut microbiota. The relative abundance of genera Pseudomonas, Congregibacter, Clostridium, Candidactus spp., Phaeobacter, Escherichia, Helicobacter, and HTCC was decreased (P < 0.05), but the genus Lactobacillus increased (P < 0.05), in LBB treatment than in cancer control. The altered gut microbiota was associated with decreased tumor incidence (80 % in GPC vs. 100 % in GCA, P = 0.0001), tumor volume (GPC 84.23 (42.75-188.4) mm(3) vs. GCA 243 (175.5-344.5) mm(3), P < 0.0001) and tumor multiplicity/count (GPC 2.92 ± 0.26 vs. GCA 6.27 ± 0.41; P < 0.0001). The expression of MUC2, ZO-1, occludin, and TLR2 was increased, but expression of TLR4, caspase 3, Cox-2, and ß-catenin was decreased by LBB treatment than in cancer control GCA (P < 0.05). CONCLUSION: Administration of LBB modulates the gut microbiota and reduces colon cancer development by decreasing tumor incidence, multiplicity/count, and volume via enhanced TLR2-improved gut mucosa epithelial barrier integrity and suppression of apoptosis and inflammation.

Colo/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Probióticos/farmacologia , Receptor 2 Toll-Like/efeitos dos fármacos , 1,2-Dimetilidrazina/toxicidade , Animais , Bifidobacterium bifidum , Bifidobacterium longum subspecies infantis , Carcinógenos/toxicidade , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Progressão da Doença , Imuno-Histoquímica , Lactobacillus acidophilus , Masculino , Mucina-2/genética , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Carga Tumoral/efeitos dos fármacos
Biomed Pharmacother ; 83: 536-541, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27447122


BACKGROUND/AIM: Probiotics have been suggested as prophylactic measure in colon carcinogenesis. This study aimed at determining the potential prophylactic activity of Lactobacillus rhamnosus GG CGMCC 1.2134 (LGG) strain on colorectal carcinogenesis via measuring its effect on Nuclear factor kappa B (NFκB) inflammatory pathway and apoptosis. MATERIALS AND METHODS: 64 Sprague Dawley rats were grouped into four as follows; Group 1 (Healthy control), Group 2 (LGG), Group 3 (cancer control Dimethyl hydrazine (DMH)) and Group 4 (LGG+DMH). LGG was administered orally to LGG and LGG+DMH groups. Colon carcinogenesis was chemically induced in LGG+DMH and DMH groups by weekly injection of 40mg/kg DMH. Animals were sacrificed after 25 weeks of experiment and tumor characteristics assessed. The change in expression of NFκB-p65, COX-2, TNFα, Bcl-2, Bax, iNOS, VEGFα, ß-catenin, Casp3 and p53 were evaluated by western blotting and qRT-PCR. RESULTS: LGG treatment significantly reduced tumor incidence, multiplicity and volume in LGG+DMH treatment group compared to DMH cancer control group. Also, LGG treatment reduced the expression of ß-catenin and the inflammatory proteins NFκB-p65, COX-2 and TNFα; the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic proteins Bax, casp3 and p53 compared with DMH group. CONCLUSION: LGG have a potential protection effect against colon carcinogenesis; inducing apoptosis and ameliorating inflammation, and may hold a promise as bio-therapeutic dietary agent.

Apoptose , Carcinogênese/patologia , Neoplasias do Colo/patologia , Células Epiteliais/patologia , Inflamação/patologia , Lactobacillus rhamnosus/fisiologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Probióticos/farmacologia , Probióticos/uso terapêutico , Ratos Sprague-Dawley , Carga Tumoral