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1.
J Anim Sci ; 99(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861855

RESUMO

The aim of the present study was to evaluate the inclusion of narasin, salinomycin, or flavomycin for 140 d on ruminal fermentation parameters, apparent nutrient digestibility, and performance of Nellore cattle offered a forage-based diet. In experiment 1, 32 rumen-cannulated Bos indicus Nellore steers [initial body weight (BW) = 220 ± 12.6 kg] were assigned to individual pens in a randomized complete block design according to their initial shrunk BW. Within block, animals were randomly assigned to 1 of 4 treatments: (1) forage-based diet without feed additives (CON; n = 8), (2) CON diet plus 13 ppm of narasin (NAR; n = 8), (3) CON diet plus 20 ppm of salinomycin (SAL; n = 8), or (4) CON diet plus 3 ppm of flavomycin (FLA; n = 8). The experimental period lasted 140 d and was divided into 5 periods of 28 d each. The inclusion of feed additives did not impact (P ≥ 0.17) dry matter intake (DMI), nutrient intake, and apparent total tract digestibility of nutrients. Nonetheless, steers fed NAR had lower (P < 0.01) molar proportion of acetate compared with CON, SAL, and FLA steers, whereas ruminal acetate tended to be greater (P < 0.09) for SAL vs. CON and FLA, but did not differ (P = 0.68) between CON vs. FLA steers. Ruminal propionate was the highest (P < 0.01) for steers fed NAR and did not differ (P > 0.20) between CON, SAL, and FLA. Consequently, NAR steers had the lowest (P < 0.01) Ac:Pr ratio, whereas Ac:Pr did not differ (P > 0.18) among CON, SAL, and FLA. Total volatile fatty acids were greater (P < 0.04) for NAR and CON vs. SAL and FLA, but did not differ (P > 0.67) among NAR vs. CON and SAL vs. FLA. In experiment 2, 164 Nellore bulls (initial shrunk BW = 299 ± 2.5 kg) were assigned to feedlot pens for 140 d in a randomized complete block design. Within block (n = 10), animals were randomly assigned to the same treatments used in experiment 1. Average daily gain was greater (P < 0.01) in NAR vs. CON, SAL, and FLA bulls, and did not differ (P > 0.12) between CON, SAL, and FLA bulls. Bulls fed NAR had greater (P < 0.02) DMI (as kg/d or % BW) and final shrunk BW compared with CON, SAL, and FLA bulls, whereas DMI and final shrunk BW did not differ (P > 0.26) between CON, SAL, and FLA bulls. Feed efficiency, however, was not impacted (P = 0.51) by any feed additives used herein. Collectively, narasin was the only feed additive that benefited performance and ruminal fermentation of Nellore animals fed a forage-based diet.


Assuntos
Bambermicinas , Rúmen , Ração Animal/análise , Animais , Bovinos , Dieta/veterinária , Suplementos Nutricionais , Digestão , Fermentação , Masculino , Piranos , Rúmen/metabolismo
2.
ACS Infect Dis ; 7(6): 1569-1577, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33826296

RESUMO

Increasing multidrug resistance in Neisseria gonorrheae is a growing public health crisis. Resistance to the last line therapies, cephalosporins and azithromycin, are of particular concern, fueling the need to discover new treatments. Here, we identified the phosphoglycolipid moenomycin from a screen of microbial natural products against drug-resistant N. gonorrheae as a potent antigonococcal agent. Moenomycin demonstrates excellent activity (MIC = 0.004-0.03 µg/mL) against a variety of multidrug-resistant N. gonorrheae. Importantly, moenomycin, thought to be a Gram-positive specific antibiotic, penetrates the Gram-negative gonococcal outer membrane. Moenomycin causes intracellular accumulation of peptidoglycan precursors, cell blebbing, and rupture of the cell envelope, all consistent with cell wall biosynthesis inhibition. Serial bacterial exposure to moenomycin for 14 days revealed slow development of resistance (MICDay14 = 0.03-0.06 µg/mL), unlike the clinically used drug azithromycin. Our results offer the potential utility of moenomycin as a lead for antigonococcal therapeutic candidates and warrant further investigation.


Assuntos
Bambermicinas , Produtos Biológicos , Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Peptidoglicano , Extratos Vegetais
3.
BMC Vet Res ; 16(1): 400, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097070

RESUMO

BACKGROUND: The excessive use of antibiotics in the livestock feed industry caused inevitable side effects of microbial resistance. Besides this residual antibiotics in animal-derived foodstuff imposed serious health problems for humans. So this study aimed to investigate the potential use of Bacillus velezensis to substitute antibiotics for poultry production. A total of 468, 49-week-old Hy-Line Brown chickens, were randomly divided into four groups the control group (regular diet), experiment group I (0.1% B. veleznesis), experiment group II (0.2% B. veleznesis), and antibiotic group (50 mg/kg flavomycin), with three replicates per group and trial period consisted on 42 days. RESULTS: The results showed that, compared with the control group, the average egg production rate and daily feed intake of experimental groups I and II increased significantly (P < 0.05), while the average egg weight was increased in experimental group II as compared to (I) (P < 0.01). The feed conversion ratio was decreased (P > 0.05) in group (II) Egg quality parameters such as yolk weight of the experimental group II was increased, but that of the antibiotic group and experiment group I was decreased, neither significant (P > 0.05). Moreover, the eggshell strength, yolk color, albumen height, and Haugh unit were significantly increased (P < 0.05). Compared with the control group, probiotic groups can increase the progesterone and motilin (P > 0.05) but decrease the secretin and cholecystokinin in the blood plasma (P > 0.05). CONCLUSIONS: This study suggested that B. velezensis can substitute in-feed-antibiotics and improved most of the study parameters significantly. Which suggested that B. velezensis has potential future application value to replace the feed antibiotics.


Assuntos
Bacillus , Galinhas/fisiologia , Ovos/normas , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Antibacterianos/administração & dosagem , Bambermicinas/administração & dosagem , Galinhas/sangue , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Casca de Ovo , Feminino , Probióticos/administração & dosagem
4.
Sci Rep ; 10(1): 12021, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694623

RESUMO

Streptomycetes are filamentous bacteria famous for their ability to produce a vast majority of clinically important secondary metabolites. Both complex morphogenesis and onset of antibiotic biosynthesis are tightly linked in streptomycetes and require series of specific signals for initiation. Cyclic dimeric 3'-5' guanosine monophosphate, c-di-GMP, one of the well-known bacterial second messengers, has been recently shown to govern morphogenesis and natural product synthesis in Streptomyces by altering the activity of the pleiotropic regulator BldD. Here we report a role of the heme-binding diguanylate cyclase SSFG_02181 from Streptomyces ghanaensis in the regulation of the peptidoglycan glycosyltransferase inhibitor moenomycin A biosynthesis. Deletion of ssfg_02181 reduced the moenomycin A accumulation and led to a precocious sporulation, while the overexpression of the gene blocked sporogenesis and remarkably improved antibiotic titer. We also demonstrate that BldD negatively controls the expression of ssfg_02181, which stems from direct binding of BldD to the ssfg_02181 promoter. Notably, the heterologous expression of ssfg_02181 in model Streptomyces spp. arrested morphological progression at aerial mycelium level and strongly altered the production of secondary metabolites. Altogether, our work underscores the significance of c-di-GMP-mediated signaling in natural product biosynthesis and pointed to extensively applicable approach to increase antibiotic production levels in streptomycetes.


Assuntos
Antibacterianos/biossíntese , Bambermicinas/biossíntese , GMP Cíclico/análogos & derivados , Proteínas de Escherichia coli/metabolismo , Engenharia Metabólica/métodos , Fósforo-Oxigênio Liases/metabolismo , Streptomyces/enzimologia , Streptomyces/crescimento & desenvolvimento , Proteínas de Bactérias/metabolismo , GMP Cíclico/genética , GMP Cíclico/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Ligantes de Grupo Heme/genética , Proteínas Ligantes de Grupo Heme/metabolismo , Morfogênese/genética , Fósforo-Oxigênio Liases/genética , Regiões Promotoras Genéticas , Sistemas do Segundo Mensageiro/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Nucleic Acids Res ; 48(3): 1583-1598, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31956908

RESUMO

Cyclic dimeric 3'-5' guanosine monophosphate, c-di-GMP, is a ubiquitous second messenger controlling diverse cellular processes in bacteria. In streptomycetes, c-di-GMP plays a crucial role in a complex morphological differentiation by modulating an activity of the pleiotropic regulator BldD. Here we report that c-di-GMP plays a key role in regulating secondary metabolite production in streptomycetes by altering the expression levels of bldD. Deletion of cdgB encoding a diguanylate cyclase in Streptomycesghanaensis reduced c-di-GMP levels and the production of the peptidoglycan glycosyltransferase inhibitor moenomycin A. In contrast to the cdgB mutant, inactivation of rmdB, encoding a phosphodiesterase for the c-di-GMP hydrolysis, positively correlated with the c-di-GMP and moenomycin A accumulation. Deletion of bldD adversely affected the synthesis of secondary metabolites in S. ghanaensis, including the production of moenomycin A. The bldD-deficient phenotype is partly mediated by an increase in expression of the pleiotropic regulatory gene wblA. Genetic and biochemical analyses demonstrate that a complex of c-di-GMP and BldD effectively represses transcription of wblA, thus preventing sporogenesis and sustaining antibiotic synthesis. These results show that manipulation of the expression of genes controlling c-di-GMP pool has the potential to improve antibiotic production as well as activate the expression of silent gene clusters.


Assuntos
Proteínas de Bactérias/genética , Bambermicinas/biossíntese , Produtos Biológicos/metabolismo , GMP Cíclico/análogos & derivados , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Proteínas de Bactérias/antagonistas & inibidores , GMP Cíclico/genética , GMP Cíclico/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Escherichia coli/genética , Deleção de Genes , Regulação Bacteriana da Expressão Gênica/genética , Nucleotídeos/genética , Peptidoglicano Glicosiltransferase/antagonistas & inibidores , Fósforo-Oxigênio Liases/genética , Sistemas do Segundo Mensageiro/genética , Streptomycetaceae/genética , Streptomycetaceae/metabolismo , Fatores de Transcrição/antagonistas & inibidores
6.
Can J Vet Res ; 83(3): 177-180, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31308589

RESUMO

The objective of this study was to assess the impact of in-feed flavophospholipol on Salmonella shedding and antibody response in nursery pigs. Weaned pigs were fed either a diet containing 4 ppm flavophospholipol (n = 16) or a non-medicated feed (n = 16) for 36 d. All pigs were orally challenged with a 2-mL dose of 108 colony-forming units (CFUs)/mL of Salmonella Typhimurium on Days 7 and 8 of the trial. On Day 36, all pigs were euthanized and samples were collected from the liver, spleen, and ileocecal lymph nodes. Fecal and tissue samples were quantitatively cultured for Salmonella and serum samples were tested for the presence of the Salmonella antibody by enzyme-linked immunosorbent assay (ELISA). There was no difference between the 2 groups in antibody response and the presence of Salmonella in feces and tissue (P > 0.05). Medicating nursery diets with flavophospholipol at 4 ppm did not appear to reduce Salmonella infection in nursery pigs.


Assuntos
Ração Animal/análise , Derrame de Bactérias/efeitos dos fármacos , Bambermicinas/farmacologia , Salmonelose Animal/prevenção & controle , Salmonella typhimurium , Doenças dos Suínos/microbiologia , Animais , Dieta/veterinária , Suínos , Doenças dos Suínos/prevenção & controle
7.
Biochem Biophys Res Commun ; 511(4): 800-805, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30837154

RESUMO

The antibiotic moenomycin A is a phosphoglycerate derivative with a C25-moenocinyl chain and a branched oligosaccharide. Formation of the C25-chain is catalyzed by the enzyme MoeN5 with geranyl pyrophosphate (GPP) and the sugar-linked 2-Z,E-farnesyl-3-phosphoglycerate (FPG) as its substrates. Previous complex crystal structures with GPP and long-chain alkyl glycosides suggested that GPP binds to the S1 site in a similar way as in most other α-helical prenyltransferases (PTs), and FPG is likely to assume a bent conformation in the S2 site. However, two FPG derivatives synthesized in the current study were found in the S1 site rather than S2 in their complex crystal structures with MoeN5. Apparently S1 is the preferred site for prenyl-containing ligand, and S2 binding may proceed only after S1 is occupied. Thus, like most trans-type PTs, MoeN5 may employ a sequential ionization-condensation-elimination mechanism that involves a carbocation intermediate.


Assuntos
Proteínas de Bactérias/metabolismo , Dimetilaliltranstransferase/metabolismo , Streptomyces/metabolismo , 2,3-Difosfoglicerato/química , 2,3-Difosfoglicerato/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/química , Bambermicinas/metabolismo , Cristalografia por Raios X , Dimetilaliltranstransferase/química , Simulação de Acoplamento Molecular , Conformação Proteica , Alinhamento de Sequência , Streptomyces/química , Especificidade por Substrato
8.
Lipids Health Dis ; 18(1): 63, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30871550

RESUMO

BACKGROUND: Both selenium (Se) and probiotic Bacillus regulate the metabolism to help defense clod stress and improve the meat quality in breeding chicks. The purpose of this study was to evaluate the effect of supplemental Se and Bacillus in the form of Se-enriched Bacillus (SECB) on the growth performance, lipid parameters, breast Se and antibiotic levels, and breast meat quality of chicken in winter cold stress. METHODS: Five hundred 1-d-old chickens were divided into five groups randomly: Control, inorganic Se, compound Bacillus, SECB, and antibiotic. The feed duration was 56 d. RESULTS: After 28 d of treatment, chicks feed SECB or compound Bacillus had higher body weights than the control, and after 56 d, chicks given either SECB or compound Bacillus had higher body weights than the control chicks or those given inorganic Se. Adding SECB to feed significantly increased the lightness, redness, and yellowness of breast meat, improved the water-holding capacity, and reduced the shear force and cooking loss. The concentration of Se in the breast muscle very significantly increased after SECB and inorganic Se supplementation, which was opposite to the concentration of flavomycin in antibiotic supplemented chicks. The antioxidative status of plasma and breast meat was significantly improved with added compound Bacillus and SECB: the total antioxidant capacity, total superoxide dismutase, and glutathione peroxidase ability in the breast muscle significantly improved, and the malondialdehyde concentration in plasma decreased. The levels of total cholesterol plasma triglyceride and very-low-density lipoprotein cholesterol in the plasma and breast muscle was decreased compared to that of the control, while the plasma high-density lipoprotein cholesterol concentration increased. CONCLUSIONS: In conclusion, SECB supplementation promoted the body growth, antioxidative status, and Se concentrations in the plasma and breast meat, and also improved the breast meat quality.


Assuntos
Antioxidantes/análise , Bacillus subtilis , Galinhas/crescimento & desenvolvimento , Resposta ao Choque Frio/efeitos dos fármacos , Probióticos/farmacologia , Selênio/farmacologia , Animais , Antibacterianos/farmacologia , Antioxidantes/metabolismo , Bambermicinas/farmacologia , Galinhas/metabolismo , Resposta ao Choque Frio/fisiologia , Qualidade dos Alimentos , Lipídeos/sangue , Distribuição Aleatória , Selênio/sangue , Selênio/farmacocinética
9.
J Antibiot (Tokyo) ; 72(2): 79-85, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30361635

RESUMO

Flavophospholipol (FPL) is an antimicrobial feed additive that has been approved for use in livestock animals and has the potential to decrease horizontal dissemination of antimicrobial resistance genes. Since previous studies showed that FPL has an inhibitory effect on plasmid transfer, in vitro experiments have proven the efficacy of FPL in reducing the conjugative transfer of plasmids encoding the extended-spectrum ß-lactamase (ESBL) and vanA genes. These are among the most important antimicrobial resistance loci known. ESBL-producing Escherichia coli and vancomycin-resistant Enterococcus faecalis (VRE) were exposed to several concentrations of FPL, and transfer frequency and plasmid curing activity were determined. FPL inhibited the conjugative transfer of plasmids harboring ESBL and vanA genes in a concentration-dependent manner in all strains. Further transfer experiments revealed that FPL could decrease or increase transfer frequency depending on plasmid type when transfer frequency was at low levels. The plasmid curing activity of FPL was also observed in ESBL-producing E. coli in a concentration-dependent manner, suggesting that they partially contribute to the inhibition of conjugative transfer. These results suggest that the use of FPL as a feed additive might decrease the dissemination of ESBL and vanA genes among livestock animals.


Assuntos
Antibacterianos/farmacologia , Bambermicinas/farmacologia , Conjugação Genética/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Escherichia coli/crescimento & desenvolvimento , Aditivos Alimentares/farmacologia , Transferência Genética Horizontal/efeitos dos fármacos , Enterococos Resistentes à Vancomicina/crescimento & desenvolvimento , Ração Animal , Proteínas de Bactérias/genética , Carbono-Oxigênio Ligases/genética , Farmacorresistência Bacteriana Múltipla/genética , Infecções por Escherichia coli/prevenção & controle , Infecções por Bactérias Gram-Positivas/prevenção & controle , Testes de Sensibilidade Microbiana , Plasmídeos/genética , Plasmídeos/fisiologia , beta-Lactamases/genética
10.
Anim Sci J ; 89(11): 1581-1590, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30175428

RESUMO

Oleum cinnamomi (OCM) is increasingly used as a feed additive in animal diets. The aim of this study was to investigate the effects of dietary supplementation with coated-OCM (cOCM) on the immunity and intestinal integrity of broiler chickens. A total of 396 one-day-old chicks were randomly assigned into six groups. The basal diets were supplemented with 50 mg/kg of flavomycin (positive control) as well as 0 (control), 50, 100, 200, and 300 mg/kg of cOCM. Compared with the control, both positive control and cOCM treatments did not improve the growth performance. Serum immunoglobulin (Ig) Y levels were decreased by flavomycin and 50 mg/kg of cOCM treatments (p < 0.05). Dietary cOCM decreased ileal secretory IgA contents at d 21 and commonly down-regulated duodenal and ileal mRNA expression of interleukin (IL)-1ß and IL-8 at d 42 (p < 0.05). The 300 mg/kg of cOCM increased jejunal ratio of villus height to crypt depth and upregulated intestinal claudin-1 expression (p < 0.05). Jejunal (at d 21) and duodenal (at d 42) mucin-2 expression was up and downregulated by both 50 and 300 mg/kg of cOCM, respectively (p < 0.05). In conclusion, dietary cOCM addition helped to maintain noninflammatory states of humoral and mucosal immunity, and improved the intestinal integrity of broiler chickens.


Assuntos
Ração Animal , Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Galinhas/imunologia , Galinhas/fisiologia , Cinnamomum zeylanicum , Dieta/veterinária , Suplementos Nutricionais , Aditivos Alimentares , Intestinos/imunologia , Intestinos/fisiologia , Óleos Vegetais/administração & dosagem , Animais , Bambermicinas , Claudina-1/metabolismo , Feminino , Imunoglobulina A Secretora/metabolismo , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Masculino , Mucina-2/metabolismo
11.
Biochimie ; 152: 1-5, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29909047

RESUMO

Peptidoglycan glycosyltransferases (GTase) of family 51 are essential enzymes for the synthesis of the glycan chains of the bacterial cell wall. They are considered potential antibacterial target, but discovery of inhibitors was hampered so far by the lack of efficient and affordable screening assay. Here we used Staphylococcus aureus MtgA to introduce a single tryptophan reporter residue in selected positions flanking the substrates binding cavity of the protein. We selected a mutant (Y181W) that shows strong fluorescence quenching in the presence of moenomycin A and two lipid II analogs inhibitors. The assay provides a simple method to study GTase-ligand interactions and can be used as primary high throughput screening of GTase inhibitors without the need for lipid II substrate or reporter ligands.


Assuntos
Ensaios de Triagem em Larga Escala , Peptidoglicano Glicosiltransferase/metabolismo , Staphylococcus aureus/enzimologia , Triptofano/metabolismo , Bambermicinas/metabolismo , Dicroísmo Circular , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Ligantes , Mutagênese Sítio-Dirigida , Peptidoglicano Glicosiltransferase/antagonistas & inibidores , Peptidoglicano Glicosiltransferase/genética , Ligação Proteica , Espectrometria de Fluorescência , Especificidade por Substrato , Triptofano/genética , Uridina Difosfato Ácido N-Acetilmurâmico/análogos & derivados , Uridina Difosfato Ácido N-Acetilmurâmico/metabolismo
12.
Vet Res Commun ; 42(3): 195-207, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29777375

RESUMO

Routine use of the antibiotic flavomycin in broiler production may lead to resistance, and alternative growth promoters are used to enhance performance. Two hundred day-old male Ross 308 broiler chicks were allocated to five dietary supplements included from d 1-42: flavomycin, three possible alternatives, a probiotic, prebiotic and a synbiotic, as well as a control treatment. There were four replicate cages of 10 birds each in each treatment. Compared with the control and antibiotics treatments, the probiotic, prebiotic and synbiotic treatments increased (p = 0.001) weight gain (64, 66, 73, 70 and 74 g/d, respectively). The synbiotic treatment reduced (p = 0.004) the feed conversion ratio, compared with the control and antibiotic treatments (1.70, 1.84, 1.83, respectively). Compared with the control and antibiotic treatments, the birds fed the synbiotic treatment had greater relative gizzard (+47%) and spleen weights (+115%), and lighter kidneys (-47%). The birds fed the symbiotic treatment also had thinner walls of the caudal gut segments. The prebiotic had the most beneficial effect on cecal microbiota, stimulating aerobic and lactic acid producing bacteria and reducing Escherichia coli bacteria. Enterococci were increased in the antibiotic treatment. We conclude that there were significant performance and health benefits of using prebiotics, probiotics and synbiotics for broilers, rather than antibiotics.


Assuntos
Antibacterianos/farmacologia , Bambermicinas/farmacologia , Galinhas/fisiologia , Suplementos Nutricionais/análise , Ração Animal/análise , Animais , Antibacterianos/administração & dosagem , Bambermicinas/administração & dosagem , Sangue/efeitos dos fármacos , Análise Química do Sangue/veterinária , Galinhas/crescimento & desenvolvimento , Galinhas/imunologia , Galinhas/microbiologia , Dieta/veterinária , Masculino , Prebióticos/administração & dosagem , Prebióticos/análise , Probióticos/administração & dosagem , Probióticos/análise , Probióticos/farmacologia , Distribuição Aleatória , Simbióticos/administração & dosagem , Simbióticos/análise , Ganho de Peso
13.
Vet Res ; 49(1): 35, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29636083

RESUMO

The minimum inhibitory concentration of bambermycin on three porcine Helicobacter suis strains was shown to be 8 µg/mL. The effect of in-feed medication with this antibiotic on the course of a gastric infection with one of these strains, the host response and the gastric microbiota was determined in mice, as all of these parameters may be involved in gastric pathology. In H. suis infected mice which were not treated with bambermycin, an increased number of infiltrating B-cells, T-cells and macrophages in combination with a Th2 response was demonstrated, as well as a decreased parietal cell mass. Compared to this non-treated, infected group, in H. suis infected mice medicated with bambermycin, gastric H. suis colonization was not altered, but a decreased number of infiltrating T-cells, B-cells and macrophages as well as downregulated expressions of IL-1ß, IL-8M, IL-10 and IFN-γ were demonstrated and the parietal cell mass was not affected. In bambermycin treated mice that were not infected with H. suis, the number of infiltrating T-cells and expression of IL-1ß were lower than in non-infected mice that did not receive bambermycin. Gastric microbiota analysis indicated that the relative abundance of bacteria that might exert unfavorable effects on the host was decreased during bambermycin supplementation. In conclusion, bambermycin did not affect H. suis colonization, but decreased gastric inflammation and inhibited the effects of a H. suis infection on parietal cell loss. Not only direct interaction of H. suis with parietal cells, but also inflammation may play a role in death of these gastric acid producing cells.


Assuntos
Antibacterianos/farmacologia , Bambermicinas/farmacologia , Infecções por Helicobacter/veterinária , Helicobacter heilmannii/fisiologia , Doenças dos Suínos/tratamento farmacológico , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais/análise , Modelos Animais de Doenças , Feminino , Infecções por Helicobacter/tratamento farmacológico , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/veterinária , Camundongos , Camundongos Endogâmicos BALB C , Células Parietais Gástricas/imunologia , Organismos Livres de Patógenos Específicos , Estômago/imunologia , Suínos
14.
J Am Chem Soc ; 140(8): 2752-2755, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29411975

RESUMO

The rise of antibiotic resistance has created a mounting crisis across the globe and an unmet medical need for new antibiotics. As part of our efforts to develop new antibiotics to target the uncharted surface bacterial transglycosylase, we report an affinity-based ligand screen method using penicillin-binding proteins immobilized on beads to selectively isolate the binders from complex natural products. In combination with mass spectrometry and assays with moenomycin A and salicylanilide analogues (1-10) as reference inhibitors, we isolated four potent antibacterials confirmed to be benastatin derivatives (11-13) and albofungin (14). Compounds 11 and 14 were effective antibiotics against a broad-spectrum of Gram-positive and Gram-negative bacteria, including Acinetobacter baumannii, Clostridium difficile, Staphylococcus aureus, and drug-resistant strains with minimum inhibitory concentrations in the submicromolar to nanomolar range.


Assuntos
Antibacterianos/farmacologia , Bambermicinas/farmacologia , Inibidores Enzimáticos/farmacologia , Glicosiltransferases/antagonistas & inibidores , Salicilanilidas/farmacologia , Xantenos/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bambermicinas/química , Bambermicinas/isolamento & purificação , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/enzimologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Glicosiltransferases/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Salicilanilidas/química , Salicilanilidas/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade , Xantenos/química , Xantenos/isolamento & purificação
15.
Can Vet J ; 59(1): 59-65, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29302104

RESUMO

A clinical trial was conducted to assess the effectiveness of in-feed flavophospholipol in reducing Salmonella shedding and antimicrobial resistance (AMR) associated with Salmonella and generic Escherichia coli in naturally infected grower-finisher pigs. Pigs were obtained from a farm with a history of salmonellosis and were housed at a research facility. Over the span of 10 weeks the pigs received either a feed containing 4 ppm of flavophospholipol (treatment, n = 25) or a non-medicated feed (control, n = 20). Weekly fecal samples were collected and cultured for Salmonella and generic E. coli. A subset of Salmonella and E. coli isolates were tested for antimicrobial susceptibility. A multilevel mixed-effects logistic regression model was used to compare the prevalence of Salmonella shedding and AMR in Salmonella and E. coli isolates in treatment and control groups. Overall, the prevalence of Salmonella shedding (P > 0.05) and AMR in Salmonella (P > 0.01) and E. coli (P > 0.005) isolates was not different between the treatment and control groups.


Assuntos
Antibacterianos/farmacologia , Bambermicinas/farmacologia , Farmacorresistência Bacteriana , Salmonelose Animal/microbiologia , Salmonella/efeitos dos fármacos , Doenças dos Suínos/microbiologia , Ração Animal/análise , Animais , Derrame de Bactérias , Dieta/veterinária , Escherichia coli , Distribuição Aleatória , Salmonella/fisiologia , Salmonelose Animal/prevenção & controle , Suínos
16.
J Anim Sci ; 95(10): 4554-4567, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29108045

RESUMO

Ionophores and antibiotics have been shown to decrease ruminal methanogenesis both in vitro and in vivo but have shown little evidence toward a sustainable means of mitigation. Feed additive rotation was proposed and investigated for methane, VFA, and microbial population response. In the present study, cannulated steers ( = 12) were fed a moderate-forage basal diet in a Calan gate facility for 13 wk. In addition to the basal diet, steers were randomly assigned to 1 of 6 treatments: 1) control, no additive; 2) bambermycin, 20 mg bambermycin/d; 3) monensin, 200 mg monensin/d; 4) the basal diet + weekly rotation of bambermycin and monensin treatments (B7M); 5) the basal diet + rotation of bambermycin and monensin treatments every 14 d (B14M); and 6) the basal diet + rotation of bambermycin and monensin treatments every 21 d (B21M). Steers were blocked by weight in a randomized complete block design where the week was the repeated measure. Rumen fluid was collected weekly for analysis ( = 13), and results were normalized according to individual OM intake (OMI; kg/d). Potential activity of methane production was not significantly different among treatments ( > 0.05). However, treatment tended to affect the CH-to-propionate ratio ( = 0.0565), which was highest in the control and lowest in the monensin, B21M, and B14M treatments (0.42 vs. 0.36, 0.36, and 0.33, respectively). The CH:propionate ratio was lowest in wk 2 and 3 ( < 0.05) but the ratio in wk 4 to 12 was not different from the ratio in wk 0. Week also affected total VFA, with total VFA peaking at wk 3 and plummeting at wk 4 (4.02 vs. 2.86 m/kg OMI; < 0.05). A significant treatment × week interaction was observed for the acetate-to-propionate (A:P) ratio, where bambermycin- and rotationally fed steers did not have a reduced A:P ratio compared with monensin-fed steers throughout the feeding period ( < 0.0001). Microbial analysis revealed significant shifts, but several predominant classes showed adaptation between 4 and 6 wk after additive initiation. There was no significant evidence to suggest that rotations of monensin and bambermycin provided additional benefits to steers consuming a moderate-forage diet at the microbial/animal and environmental level versus those continuously fed.


Assuntos
Antibacterianos/administração & dosagem , Bovinos/fisiologia , Suplementos Nutricionais , Ácidos Graxos Voláteis/metabolismo , Ionóforos/administração & dosagem , Metano/metabolismo , Ração Animal , Animais , Bambermicinas/administração & dosagem , Bovinos/microbiologia , Dieta/veterinária , Fermentação , Masculino , Monensin/administração & dosagem , Distribuição Aleatória , Rúmen/metabolismo , Rúmen/microbiologia
17.
J Anim Sci ; 94(10): 4307-4314, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27898865

RESUMO

Two experiments were designed to evaluate the effects of monensin, virginiamycin, and flavomycin on growth performance, carcass characteristics, apparent total tract nutrient digestibility, and rumen fermentation of zebu cattle fed a no-roughage finishing diet (whole shelled corn [WSC] based). In Exp. 1, 100 crossbred bulls (; 392 kg [SD 46.8] average initial BW) were blocked by initial BW in a 101-d feedlot trial. Five treatments were evaluated using 4 pens per treatment (5 bulls/pen): monensin at 30 mg/kg DM, virginiamycin at 25 mg/kg DM, monensin at 20 mg/kg DM plus virginiamycin at 25 mg/kg DM, flavomycin at 4.4 mg/kg DM, and monensin at 20 mg/kg DM plus flavomycin at 2.2 mg/kg DM. There were no differences in growth performance (final BW, ADG, DMI, and G:F; ≥ 0.527) and carcass characteristics (HCW, dressing percent, and 12th-rib fat; ≥ 0.235) among treatments. In Exp. 2, 7 ruminally fistulated steers were used in a 7 × 7 Latin square design to evaluate the 5 treatments of Exp. 1 and 2 additional treatments: monensin at 30 mg/kg DM plus virginiamycin at 25 mg/kg DM and monensin at 20 mg/kg DM plus flavomycin at 4.4 mg/kg DM. Experimental periods were 14 d in length (9 d of adaptation and 5 d of measurements). Apparent total tract DM, OM, CP, and NDF digestibilities were similar among treatments ( ≥ 0.224). There was no treatment effect ( ≥ 0.253) in rumen fermentation responses (ruminal pH, rumen ammonia nitrogen, VFA, and number of protozoa). In conclusion, no evidence of benefits to cattle fed a no-roughage WSC-based diet was found to support the use of monensin combined with virginiamycin or flavomycin in the doses tested herein.


Assuntos
Bambermicinas/farmacologia , Bovinos , Dieta/veterinária , Fibras na Dieta , Monensin/farmacologia , Virginiamicina/farmacologia , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Antibacterianos/farmacologia , Composição Corporal/efeitos dos fármacos , Digestão/fisiologia , Fermentação , Trato Gastrointestinal/efeitos dos fármacos , Masculino , Inibidores da Síntese de Proteínas/farmacologia , Ionóforos de Próton/farmacologia , Rúmen/metabolismo
18.
Appl Microbiol Biotechnol ; 100(17): 7629-38, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27344593

RESUMO

Moenomycins are phosphoglycolipid antibiotics notable for their extreme potency, unique mode of action, and proven record of use in animal nutrition without selection for resistant microflora. There is a keen interest in manipulation of structures of moenomycins in order to better understand their structure-activity relationships and to generate improved analogs. Only two almost identical moenomycin biosynthetic gene clusters are known, limiting our knowledge of the evolution of moenomycin pathways and our ability to genetically diversify them. Here, we report a novel gene cluster (tchm) that directs production of the phosphoglycolipid teichomycin in Actinoplanes teichomyceticus. Its overall genetic architecture is significantly different from that of the moenomycin biosynthesis (moe) gene clusters of Streptomyces ghanaensis and Streptomyces clavuligerus, featuring multiple gene rearrangements and two novel structural genes. Involvement of the tchm cluster in teichomycin biosynthesis was confirmed via heterologous co-expression of amidotransferase tchmH5 and moe genes. Our work sets the background for further engineering of moenomycins and for deeper inquiries into the evolution of this fascinating biosynthetic pathway.


Assuntos
Actinobacteria/genética , Antibacterianos/biossíntese , Bambermicinas/biossíntese , Família Multigênica/genética , Oligossacarídeos/biossíntese , Teicoplanina/biossíntese , Actinobacteria/metabolismo , Vias Biossintéticas/genética , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Bactérias Gram-Positivas/efeitos dos fármacos , Oligossacarídeos/genética , Relação Estrutura-Atividade
19.
Biochem Pharmacol ; 93(2): 141-50, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25462814

RESUMO

The glycosyltransferases of family 51 (GT51) catalyze the polymerization of lipid II to form linear glycan chains, which, after cross linking by the transpeptidases, form the net-like peptidoglycan macromolecule. The essential function of the GT makes it an attractive antimicrobial target; therefore a better understanding of its function and its mechanism of interaction with substrates could help in the design and the development of new antibiotics. In this work, we have used a surface plasmon resonance Biacore(®) biosensor, based on an amine derivative of moenomycin A immobilized on a sensor chip surface, to investigate the mechanism of binding of substrate analogous inhibitors to the GT. Addition of increasing concentrations of moenomycin A to the Staphylococcus aureus MtgA led to reduced binding of the protein to the sensor chip as expected. Remarkably, in the presence of low concentrations of the most active disaccharide inhibitors, binding of MtgA to immobilized moenomycin A was found to increase; in contrast competition with moenomycin A occurred only at high concentrations. This finding suggests that at low concentrations, the lipid II analogs bind to the acceptor site and induce a cooperative binding of moenomycin A to the donor site. Our results constitute the first indication of the existence of a positive cooperativity between the acceptor and the donor sites of peptidoglycan GTs. In addition, our study indicates that a modification of two residues (L119N and F120S) within the hydrophobic region of MtgA can yield monodisperse forms of the protein with apparently no change in its secondary structure content, but this is at the expense of the enzyme function.


Assuntos
Interações Microbianas/fisiologia , Peptidoglicano Glicosiltransferase/química , Peptidoglicano Glicosiltransferase/metabolismo , Staphylococcus aureus/metabolismo , Bambermicinas/metabolismo , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ressonância de Plasmônio de Superfície/métodos
20.
Chem Biol Drug Des ; 84(6): 685-96, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24890564

RESUMO

Peptidoglycan glycosyltransferase (PGT) has been shown to be an important pharmacological target for the inhibition of bacterial cell wall biosynthesis. Structure-based virtual screening of about 3,000,000 commercially available compounds against the crystal structure of the glycosyltransferase (GT) domain of the Staphylococcus aureus penicillin-binding protein 2 (S. aureus PBP2) resulted in identification of an isatin derivative, 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(m-tolyl)acetamide (4) as a novel potential GT inhibitor. A series of 4 derivatives were synthesized. Several compounds showed more active antimicrobial activity than the initial hit compound 4, in particular 2-(3-(2-carbamimidoylhydrazono)-2-oxoindolin-1-yl)-N-(3-nitrophenyl)acetamide (4l), against Gram-positive Bacillus subtilis and S. aureus with MIC values of 24 and 48 µg/mL, respectively. Saturation transfer difference (STD) NMR study revealed that there is a binding contact between 4l and the GT domain of S. aureus PBP2. Competitive STD-NMR further proved that 4l and moenomycin A bind to GT domain in a competitive manner. Molecular docking study suggests a potential binding pocket of 4l in the GT domain of S. aureus PBP2. Taken together, compound 4l would provide a new scaffold for further development of potent GT inhibitors.


Assuntos
Antibacterianos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Isatina/química , Peptidoglicano Glicosiltransferase/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bambermicinas/química , Bambermicinas/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isatina/síntese química , Isatina/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Peptidoglicano Glicosiltransferase/metabolismo , Estrutura Terciária de Proteína , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade
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