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1.
J Plast Reconstr Aesthet Surg ; 73(9): 1747-1757, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32278659

RESUMO

BACKGROUND: Capsular contracture remains a problem following breast implant surgery. Although impact of biofilm and implant surface on capsule formation has been demonstrated, interaction of microorganisms with different surface types has not been clarified yet. We aimed to compare the ability of biofilm formation of implants with different surfaces, under standard conditions and to demonstrate its impact on capsular contracture. METHODS: Twenty-four rats were divided into four groups. Mini-implants with three different surfaces (fine-textured, rough-textured and polyurethane) were placed on the dorsum of each rat. In Group-1, sterile implants were placed in submuscular pockets. In Group-2, implants were incubated in Staphylococcus epidermidis medium before implantation. In Group-3, before implantation, implants were immersed in Rifamycin solution following bacterial contamination. In Group-4, sterile implants were immersed in Rifamycin solution before implantation, and served as the control group. Rats were sacrificed at three months. Clinical, microbiological, histological and immunohistochemical evaluations were performed. RESULTS: Capsule contracture developed only on infected rough-textured implants. Rough-textured and polyurethane implants showed more biofilm formation than fine-textured implants. Capsule thickness and inflammatory cell density were higher on rough-textured implants compared to fine-textured implants (p = 0.004). Actin sequence was parallel and concentric on fine-textured and rough-textured implants; but was in irregular array on polyurethane implants. CONCLUSION: In presence of bacterial contamination, rough-textured implants have the most propensity of developing capsular contracture comparing to fine-textured and polyurethane implants at three months after implantation. Despite high bacterial load and biofilm formation, polyurethane implants are resistant to capsule contracture due to surface characteristics.


Assuntos
Biofilmes , Implantes de Mama , Contratura Capsular em Implantes/microbiologia , Desenho de Prótese , Propriedades de Superfície , Animais , Antibacterianos/farmacologia , Materiais Revestidos Biocompatíveis , Modelos Animais de Doenças , Feminino , Poliuretanos , Ratos Long-Evans , Rifamicinas/farmacologia , Staphylococcus epidermidis
2.
Biochem Pharmacol ; 174: 113829, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32001236

RESUMO

Nicotinic acid (NA) and nicotinamide (NAM) are biosynthetic precursors of nicotinamide adenine dinucleotide (NAD+) - a physiologically important coenzyme that maintains the redox state of cells. Mechanisms driving their entry into cells are not well understood. Here we evaluated the hepatic uptake mechanism(s) of NA and NAM using transporter-transfected cell systems and primary human hepatocytes. NA showed robust organic anion transporter (OAT)2-mediated transport with an uptake ratio (i.e., ratio of accumulation in transfect cells to wild-type cells) of 9.7 ± 0.3, and a Michaelis-Menten constant (Km) of 13.5 ± 3.3 µM. However, no transport was apparent via other major hepatic uptake and renal secretory transporters, including OAT1/3/4, organic anion transporting polypeptide (OATP)1B1/1B3/2B1, sodium-taurocholate co-transporting polypeptide, organ cation transporter 1/2/3. OAT2-specific transport of NA was inhibited by ketoprofen and indomethacin (known OAT2 inhibitors) in a concentration-dependent manner. Similarly, NA uptake into primary human hepatocytes showed pH- and concentration-dependence and was subject to inhibition by specific OAT2 inhibitors. Unlike NA, NAM was not transported by the hepatic and renal solute carriers upon assessment in transfected cells, although its uptake into human hepatocytes was significantly inhibited by excess unlabelled NAM and a pan-SLC inhibitor (rifamycin SV 1 mM). In conclusion, these studies demonstrate, for the first time, a specific transport mechanism for NA uptake in the human liver and suggest that OAT2 (SLC22A7) has a critical role in its physiological and pharmacological functions.


Assuntos
Hepatócitos/metabolismo , Fígado/metabolismo , Niacina/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Rifamicinas/farmacologia
3.
Microbiol Res ; 228: 126302, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442862

RESUMO

Endophytic bacteria isolated from cactus were characterized and assessed for their capability to induce drought tolerance and growth promotion in tomato. A total of 191-bacteria representing 13-genera and 18-species were isolated from wild cactus, Euphorbia trigonas. Bacillus (58), Lysinibacillus (36), Enterobacter (29), Stenotrophomonas (18), Lelliottia (12) and Pseudomonas (12) were the most represented genera. 16S rDNA sequence (>1400-bp) comparison placed the bacterial isolates with Bacillus xiamenensis; Bacillus megaterium; Bacillus cereus; Bacillus amyloliquefaciens; Bacillus velezensis; Brevibacillus brevis; Lysinibacillus fusiformis; Enterobacter cloacae; Lelliottia nimipressuralis; Proteus penneri; Sphingobacterium multivorum; Klebsiella pneumoniae; Pseudomonas putida; Pseudomonas aeruginosa; Stenotrophomonas maltophilia; Citrobacter freundii; Chryseobacterium indologenes and Paracoccus sp. Bacillus xiamenensis was identified for the first time as plant endophyte. Upon bacterization, the endophytes triggered germination and growth promotion in tomato as indicated by 118 % and 52 % more root-biomass under drought-free and drought-induced conditions, respectively. Bacillus amyloliquefaciens CBa_RA37 and B. megaterium RR10 displayed broad spectrum endophytism in tomato. Bacterization of tomato with cactus endophyte showed altered oxidative status, stomatal and photosystem II functioning, internal leaf temperature and relative water content suggestive of physiological de-stressing from moisture stress. Activity of oxidative stress enzymes such as guaiacol peroxidase and catalase was also indicative of endophyte assisted de-stressing of tomato. Re-irrigation on 20-days of drought infliction showed 86.9% recovery of B. amyloliquefaciens CBa_RA37 primed tomato when non-primed plantlets succumbed. The cactus endophytic bacterial strain B. amyloliquefaciens CBa_RA37 showed promise for low-cost, efficient and environmentally friendly bio-inoculant technology to mitigate drought in arid zones of Asian and African continents.


Assuntos
Cactaceae/microbiologia , Secas , Endófitos/classificação , Endófitos/isolamento & purificação , Endófitos/fisiologia , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/microbiologia , Desenvolvimento Vegetal , Aclimatação , Bacillus/classificação , Bacillus/genética , Bacillus/isolamento & purificação , Bacillus/fisiologia , Biomassa , Camarões , DNA Ribossômico/genética , Clima Desértico , Endófitos/genética , Filogenia , Folhas de Planta , Raízes de Plantas , RNA Ribossômico 16S/genética , Rifamicinas/farmacologia , Análise de Sequência , Microbiologia do Solo , Estresse Fisiológico
4.
ACS Infect Dis ; 5(10): 1754-1763, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31461259

RESUMO

Rifamycins are a group of macrocyclic antibiotics mainly used for the treatment of various bacterial infections including tuberculosis. Spectroscopic studies of rifamycins evidence the formation of temperature- and solvent-dependent equilibria between A-, B-, and C-type conformers in solutions. The B- and C-type conformers of rifamycin antibiotics are exclusively formed in the presence of water molecules. A- and B-type conformers exhibit a hydrophilic and "open" ansa-bridge nature whereas the C-type conformer is more lipophilic due to the presence of a "closed" ansa-bridge structure. The involvement of the lactam moiety of the ansa-bridge in intramolecular H-bonds within rifapentine and rifampicin implicates the formation of a more hydrophilic A-type conformer. In contrast to rifampicin and rifapentine, for rifabutin and rifaximin, the "free" lactam group enhances conformational flexibility of the ansa-bridge, thereby enabling interconversion between A- and C-type conformers. In turn, an equilibrium between A- and C-type conformers for rifamycins improves their adaptation to the changing nature of bacteria cell membranes, especially those of Gram-negative strains and/or to efflux pump systems.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Rifamicinas/química , Rifamicinas/farmacologia , Água/química , Transporte Biológico/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA , Bactérias Gram-Negativas/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Modelos Químicos , Conformação Molecular , Permeabilidade , Rifampina/análogos & derivados , Rifamicinas/classificação , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 29(16): 2112-2115, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31281018

RESUMO

Infections due to rapidly growing mycobacteria (RGM), and in particular the RGM species Mycobacterium abscessus (Mab), are very difficult to treat and reports on novel therapeutic options are scarce. A hallmark of all pathogenic RGM species is their resistance to the four first-line drugs used to treat infections with Mycobacterium tuberculosis including rifampicin. This study demonstrates that modification of the rifampicin scaffold can restore rifampicin activity against the three most commonly isolated pathogenic RGM species including Mab. We also note that the structure-activity relationship for Mab is different as compared to the non-pathogenic RGM species Mycobacterium smegmatis.


Assuntos
Antibacterianos/farmacologia , Mycobacterium/efeitos dos fármacos , Rifamicinas/farmacologia , Antibacterianos/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Rifamicinas/síntese química , Relação Estrutura-Atividade
7.
MAbs ; 11(6): 1162-1174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31219754

RESUMO

DSTA4637S, a novel THIOMAB™ antibody-antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy for complicated S. aureus bloodstream infections. DSTA4637S is composed of a monoclonal THIOMABTM IgG1 recognizing S. aureus linked to a rifamycin-class antibiotic (dmDNA31) via a protease-cleavable linker. The pharmacokinetics (PK) of DSTA4637A (a liquid formulation of DSTA4637S) and its unconjugated antibody MSTA3852A were characterized in rats and monkeys. Systemic concentrations of three analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured to describe complex TAC PK in nonclinical studies. In rats and monkeys, following intravenous administration of a single dose of DSTA4637A, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential, characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested, and ac-dmDNA31 cleared 2-3 times faster than TAb. Unconjugated dmDNA31 plasma concentrations were low (<4 ng/mL) in every study regardless of dose. In this report, an integrated semi-mechanistic PK model for two analytes (TAb and ac-dmDNA31) was successfully developed and was able to well describe the complicated DSTA4637A PK in mice, rats and monkeys. DSTA4637S human PK was predicted reasonably well using this model with allometric scaling of PK parameters from monkey data. This work provides insights into PK behaviors of DSTA4637A in preclinical species and informs clinical translatability of these observed results and further clinical development. Abbreviations: ADC: Antibody-drug conjugate; AUCinf: time curve extrapolated to infinity; ac-dmDNA31: antibody-conjugated dmDNA31; Cmax: maximum concentration observed; DAR: drug-to-antibody ratio; CL: clearance; CLD: distribution clearance; CL1: systemic clearance of all DAR species; kDC: deconjugation rate constant; PK: Pharmacokinetics; IV: Intravenous; IgG: Immunoglobulin G; mAb: monoclonal antibody; S. aureus: Staphylococcus aureus; TAC: THIOMABTM antibody-antibiotic conjugate; TDC: THIOMABTM antibody-drug conjugate; TAb: total antibody; t1/2, λz: terminal half-life; vc linker: valine-citrulline linker; Vss: volume of distribution at steady state; Vc: volume of distribution for the central compartment; Vp: the volume of distribution for the peripheral compartment.


Assuntos
Anticorpos Antibacterianos , Anticorpos Monoclonais , Imunoconjugados , Imunoglobulina G , Rifamicinas , Staphylococcus aureus/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/farmacologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Imunoconjugados/imunologia , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Macaca fascicularis , Masculino , Ratos , Ratos Sprague-Dawley , Rifamicinas/imunologia , Rifamicinas/farmacocinética , Rifamicinas/farmacologia
8.
Drug Metab Pharmacokinet ; 34(3): 172-180, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31101589

RESUMO

Rifamycin SV (rifamycin), is a member of the ansamycin family of antimicrobial compounds which kills bacteria commonly associated with infectious diarrhea and other enteric infections. Rifamycin has been found to be effective in experimental animal models of gut inflammation and its efficacy in these settings has been attributed partially to immunomodulatory non-bactericidal activities. This study aimed to further evaluate the anti-inflammatory activities of rifamycin by analyzing its effect on two key regulators of inflammation: PXR and NFκB. Rifamycin stimulated PXR transcriptional activity in two PXR reporter cell lines and induced expression of two genes known to be regulated by PXR and are directly involved in cellular detoxification: CYP3A4 and PgP. Moreover, CYP3A4 metabolic activity was induced by rifamycin in HepG2 cells. Rifamycin also antagonized TNFα and LPS-induced NFκB activities and inhibited IL1ß-induced synthesis of inflammatory chemokine, IL8. Although reciprocal regulation of PXR and NFkB by rifamycin was not directly addressed, the data suggest that in the absence of PXR, inhibition of NFκB by rifamycin is not dependent on PXR stimulation. Thus, rifamycin exhibits potent anti-inflammatory activities, characterized by in vitro PXR activation and concomitant CYP3A4 and PgP induction, in parallel with potent NFκB inhibition and concomitant IL8 inhibition.


Assuntos
Anti-Inflamatórios/farmacologia , NF-kappa B/antagonistas & inibidores , Receptor de Pregnano X/genética , Rifamicinas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Células CACO-2 , Técnicas de Cultura de Células , Citocromo P-450 CYP3A/genética , Células HT29 , Células Hep G2 , Humanos , NF-kappa B/genética , Transdução de Sinais
10.
Eur J Med Chem ; 167: 96-104, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30769243

RESUMO

New rifamycin congeners (1-33) with incorporated amine and hydrazone substituents leading to lipophilic and/or basic nature and altered rigidity of modified C(3) arm were synthesized and structurally characterized in detail. NMR spectroscopic studies at different temperatures indicate two types of structures of rifamycin congeners that are realized in solution: zwitterionic and non-ionic forms in dependence of the basicity of modified C(3) arm. The presence of rifamycin congeners in these two possible forms has a significant impact on the physico-chemical parameters such as lipophilicity (clogP) and water solubility and different binding mode of the C(3) arm of antibiotic at RNAP binding pocket (molecular target) leading to different antibacterial potency. The highest antibacterial potency against S. aureus (including MRSA and MLSB strains) and S. epidermidis strains, even higher than reference rifampicin (Rif) and rifaximin (Rifx) antibiotics, was found for rifamycin congeners bearing at the C(3) arm relatively rigid and basic substituents (bipiperidine and guanidine groups). These modifications provide favorable docking mode and excellent water solubility resulting in high potency (MICs 0.0078 µg/mL what gives ∼ 8.5 nM), irrespective whether rifamycin congener is a tertiary amine (15) or hydrazone (29). In turn, for a higher antibacterial potency of rifamycin congeners against E. faecalis strain (MICs 0.5 µg/mL that is 0.6 µM) as compared to Rif and Rifx, the most crucial factors are: bulkiness and the lipophilic character of the end of the C(3) rebuilt arm.


Assuntos
Aminas/química , Antibacterianos/síntese química , Hidrazonas/química , Simulação de Acoplamento Molecular , Rifamicinas/química , Rifamicinas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Rifampina/farmacologia , Rifamicinas/síntese química , Rifamicinas/metabolismo , Solubilidade , Relação Estrutura-Atividade
11.
Org Lett ; 21(4): 900-903, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30714736

RESUMO

This study reported the isolation and characterization of 11 rifamycin congeners including six new ones (1-6) from the agar fermentation extract of Amycolatopsis mediterranei S699. Compounds 1 and 2 are rifamycin glycosides named as rifamycinosides A and B, respectively. Their polyketide skeleton represents a novel cleavage pattern of the rifamycin ansa chain. Compounds 6 and 8 showed potential T3SS inhibitory activity, and 6 induced G2/M phase arrest and caused DNA damage in HCT116 cells.


Assuntos
Actinobacteria/química , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Rifamicinas/farmacologia , Sistemas de Secreção Tipo III/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antifúngicos/química , Antifúngicos/isolamento & purificação , Candida albicans/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Células HCT116 , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Rifamicinas/química , Rifamicinas/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Sistemas de Secreção Tipo III/metabolismo
12.
Nat Commun ; 9(1): 4147, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297823

RESUMO

Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (RifR). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant RifR mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of RifR RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms.


Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , Tuberculose/prevenção & controle , Aminobenzoatos/química , Antibióticos Antituberculose/biossíntese , Antibióticos Antituberculose/química , Antibióticos Antituberculose/farmacologia , Bactérias/genética , Bactérias/metabolismo , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/metabolismo , Farmacorresistência Bacteriana/genética , Humanos , Hidroxibenzoatos/química , Metagenômica/métodos , Estrutura Molecular , Mutação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Rifampina/química , Rifampina/metabolismo , Rifamicinas/química , Rifamicinas/farmacologia , Microbiologia do Solo , Tuberculose/microbiologia
13.
Mol Cell ; 72(2): 263-274.e5, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30244835

RESUMO

Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered-compared with rifampicin-conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa bridge substituents make additional contacts with a separate, hydrophobic pocket of RNA polymerase and preclude the formation of initial dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance.


Assuntos
Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Rifabutina/farmacologia , Rifampina/farmacologia , Rifamicinas/farmacologia , Antituberculosos/farmacologia , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Humanos , Testes de Sensibilidade Microbiana/métodos , Mutação/efeitos dos fármacos , Mutação/genética , Mycobacterium tuberculosis/genética , Thermus thermophilus/efeitos dos fármacos , Thermus thermophilus/genética
14.
Sci Rep ; 8(1): 11897, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093677

RESUMO

Multiple mutations in the ß subunit of the RNA polymerase (rpoß) of Mycobacterium tuberculosis (Mtb) are the primary cause of resistance to rifamycin (RIF). In the present study, bifidobacterial rpoß sequences were analyzed to characterize the mutations that contribute to the development of intrinsic resistance to RIF, isoniazid, streptomycin and pyrazinamide. Sequence variations, which mapped to cassettes 1 and 2 of the rpoß pocket, are also found in multidrug-resistant Mtb (MDR Mtb). Growth curves in the presence of osmolytes and different concentrations of RIF showed that the bacteria adapted rapidly by shortening the growth curve lag time. Insight into the adapted rpoß DNA sequences revealed that B. adolescentis harbored mutations both in the RIF pocket and in regions outside the pocket. The minimum inhibitory concentrations (MICs) and mutant prevention concentrations (MPCs) indicated that B. longum, B. adolescentis and B. animalis are resistant to antitubercular drugs. 3D-homology modeling and binding interaction studies using computational docking suggested that mutants had reduced binding affinity towards RIF. RIF-exposed/resistant bacteria exhibited variant protein profiles along with morphological differences, such as elongated and branched cells, surface conversion from rough to smooth, and formation of a concentrating ring.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Bifidobacterium adolescentis/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , RNA Polimerase II/metabolismo , Antituberculosos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Bifidobacterium adolescentis/genética , Bifidobacterium adolescentis/crescimento & desenvolvimento , Sítios de Ligação/genética , Farmacorresistência Bacteriana Múltipla/genética , Isoniazida/metabolismo , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Domínios Proteicos , Pirazinamida/metabolismo , Pirazinamida/farmacologia , RNA Polimerase II/química , RNA Polimerase II/genética , Rifamicinas/metabolismo , Rifamicinas/farmacologia
15.
Contrast Media Mol Imaging ; 2018: 3064751, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30154685

RESUMO

The bile acid analogue [18F]LCATD (LithoCholic Acid Triazole Derivative) is transported in vitro by hepatic uptake transporters such as OATP1B1 and NTCP and efflux transporter BSEP. In this in vivo "proof of principle" study, we tested if [18F]LCATD may be used to evaluate drug-drug interactions (DDIs) caused by inhibition of liver transporters. Hepatic clearance of [18F]LCATD in rats was significantly modified upon coadministration of rifamycin SV or sodium fusidate, which are known to inhibit clinically relevant uptake transporters (OATP1B1, NTCP) and canalicular hepatic transporters (BSEP) in humans. Treatment with rifamycin SV (total dose 62.5 mg·Kg-1) reduced the maximum radioactivity of [18F]LCATD recorded in the liver from 14.2 ± 0.8% to 10.2 ± 0.9% and delayed t_max by 90 seconds relative to control rats. AUCliver 0-5 min, AUCbile 0-10 min and hepatic uptake clearance CLuptake,in vivo of rifamycin SV treated rats were significantly reduced, whereas AUCliver 0-30 min was higher than in control rats. Administration of sodium fusidate (30 mg·Kg-1) inhibited the liver uptake of [18F]LCATD, although to a lesser extent, reducing the maximum radioactivity in the liver to 11.5 ± 0.3%. These preliminary results indicate that [18F]LCATD may be a good candidate for future applications as an investigational tracer to evaluate altered hepatobiliary excretion as a result of drug-induced inhibition of hepatic transporters.


Assuntos
Interações Medicamentosas , Radioisótopos de Flúor/química , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Tomografia por Emissão de Pósitrons , Triazóis/química , Animais , Artérias/metabolismo , Ductos Biliares/metabolismo , Feminino , Radioisótopos de Flúor/sangue , Radioisótopos de Flúor/farmacocinética , Ácido Fusídico/farmacologia , Cinética , Especificidade de Órgãos , Ratos Sprague-Dawley , Rifamicinas/farmacologia , Distribuição Tecidual , Triazóis/sangue , Triazóis/farmacocinética
16.
Expert Opin Investig Drugs ; 27(6): 543-551, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29865875

RESUMO

INTRODUCTION: The gastrointestinal tract acts as a functional unit organized as a semipermeable multilayer system, in which commensal gut microbiota represents the anatomical barrier. Recently, several studies have highlighted the involvement of gut microbiota in inflammatory bowel diseases (IBD) pathogenesis, in sustaining gut barrier chronic inflammation, and in conditioning disease course and therapeutical response. This evidence provides a rationale for treating patients with gut microbiota modifiers. Among these, Rifaximin represents a non-traditional antibiotic able to act as a 'eubiotic' on intestinal barrier. AREAS COVERED: The purpose of this narrative review is to explore the impact of Rifaximin on gut barrier and gut microbiota in IBD, in particular in Crohn's disease (CD), and to analyze its potential therapeutic applications. EXPERT OPINION: The possibility of a beneficial activity of Rifaximin in chronic intestinal inflammation and CD has been debated and evaluated with different studies having obtained promising but still preliminary data. Larger trials are therefore needed. This gut-specific antibiotic could represent an alternative to systemic antibiotics thanks to its favorable safety profile and promising efficacy data. Rifaximin could exert, when appropriate, a synergic effect with immunomodulators in IBD, acting on both the microbial and the immunological sides of gut barrier impairment.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Rifamicinas/administração & dosagem , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/farmacologia , Doença de Crohn/microbiologia , Doença de Crohn/fisiopatologia , Sinergismo Farmacológico , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Fatores Imunológicos/administração & dosagem , Inflamação/tratamento farmacológico , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/fisiopatologia , Rifamicinas/efeitos adversos , Rifamicinas/farmacologia , Rifaximina
17.
Chem Biol Interact ; 289: 75-80, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29709589

RESUMO

In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism. In this study, surface pressure-area isotherms, as well as spectroscopic and microscopic techniques of characterization of phospholipid monolayers at the air/water interface were used to gain insight into drug-membrane interactions. Differences in the affinity for lipid membranes for both drugs, given by the vibration frequency of characteristic chemical groups in the lipid, as well as by reflectivity and mean molecular area of the monolayer, seem to be due to the N-alkyl substituent and can contribute to provide a molecular explanation as why they pose different choices in the chemotherapy against the deadliest infectious disease, tuberculosis.


Assuntos
Membranas Artificiais , Piperazinas/química , Rifamicinas/química , Rifamicinas/farmacologia , 1,2-Dipalmitoilfosfatidilcolina/química , Microscopia , Piperazina , Pressão , Rifampina/análogos & derivados , Rifampina/química , Rifampina/farmacologia , Análise Espectral , Temperatura , Vibração
18.
Cell Mol Biol (Noisy-le-grand) ; 64(5): 149-156, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29729709

RESUMO

The study investigated 110 Enterobacteriaceae isolates from broiler chickens isolated from Sharkia poultry farms and analyzed the isolates antimicrobial resistance and the presence of integrons as a potential basis for this resistance. Antibiotic susceptibilities against 12 different antibiotics were determined by the disk diffusion method. Prevalences and classes of integrons were then detected in multi-drug resistant (MDR) strains using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by sequencing of the variable parts. Fifty-three isolates were MDR (resistant to three or more antimicrobial agents). High resistance was detected for rifamycin (82.7%), erythromycin (67.2%), and amoxicillin-clavulanic acid (63%). Classes 1 and 2 integrons were detected in 38 of 53 MDR Enterobacteriaceae isolates of which the most common were Salmonella species (n=19), followed by Escherichia coli (12), Klebsiella pneumoniae (3), Proteus species (3), and Citrobacter freundii (1). Three isolates only harbored class 1 integrons while the remaining 35 isolates carried class 2.  All class 1 integron positive isolates exhibited the same gene cassettes arrangements: 1.) dfrA12-orfF-aadA27 (1.6 kbp); 2.) aadA23 (1.0 kbp); and 3.) dfrA15 (0.8 kbp). Moreover, four different gene cassettes were identified within class 2 integrons: 1.) dfrA1-sat2-aadA30 (2 kbp) in all isolates; 2.) sat2-aadA1 (1.7 kbp) in only one isolate; 3.) catB2 (0.9 kbp) in four isolates; and 4.) a new variant of sat2 (0.65 kbp) in three isolates. Efforts should be made to introduce surveillance programs for monitoring antimicrobial resistance that could potentially be transmitted from broiler chickens to human via integrons.


Assuntos
Farmacorresistência Bacteriana/genética , Infecções por Enterobacteriaceae/veterinária , Enterobacteriaceae/genética , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Integrons , Doenças das Aves Domésticas/epidemiologia , Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Animais , Antibacterianos/farmacologia , Galinhas , Egito/epidemiologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/epidemiologia , Infecções por Enterobacteriaceae/microbiologia , Eritromicina/farmacologia , Fazendas , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Aves Domésticas , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/microbiologia , Rifamicinas/farmacologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-29661864

RESUMO

Mycobacterium tuberculosis is a critical threat to human health due to the increased prevalence of rifampin resistance (RMPr). Fitness defects have been observed in RMPr mutants with amino acid substitutions in the ß subunit of RNA polymerase (RNAP). In clinical isolates, this fitness defect can be ameliorated by the presence of secondary mutations in the double-psi ß-barrel (DPBB) domain of the ß' subunit of RNAP. To identify factors contributing to the fitness defects observed in vivo, several in vitro RNA transcription assays were utilized to probe initiation, elongation, termination, and 3'-RNA hydrolysis with the wild-type and RMPrM. tuberculosis RNAPs. We found that the less prevalent RMPr mutants exhibit significantly poorer termination efficiencies relative to the wild type, an important factor for proper gene expression. We also found that several mechanistic aspects of transcription of the RMPr mutant RNAPs are impacted relative to the wild type. For the clinically most prevalent mutant, the ßS450L mutant, these defects are mitigated by the presence of secondary/compensatory mutations in the DPBB domain of the ß' subunit.


Assuntos
RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana Múltipla/genética , Aptidão Genética/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Elongação Traducional da Cadeia Peptídica/genética , Rifampina/farmacologia , Rifamicinas/farmacologia , Sequência de Aminoácidos/genética , Substituição de Aminoácidos/genética , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Terminação Traducional da Cadeia Peptídica/genética , Domínios Proteicos/genética , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia
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