A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.

Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone

A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of β-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3

A CHEOPS-enhanced view of the HD 3167 system

A. C. C. and T. G. W. acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant number ST/R003203/1.Much remains to be understood about the nature of exoplanets smaller than Neptune, most of which have been discovered in compact multi-planet systems. With its inner ultra-short period planet b aligned with the star and two larger outer planets d-c on polar orbits, the multi-planet system HD 3167 features a peculiar architecture and offers the possibility to investigate both dynamical and atmospheric evolution processes. To this purpose we combined multiple datasets of transit photometry and radial velocimetry (RV) to revise the properties of the system and inform models of its planets. This effort was spearheaded by CHEOPS observations of HD 3167b, which appear inconsistent with a purely rocky composition despite its extreme irradiation. Overall the precision on the planetary orbital periods are improved by an order of magnitude, and the uncertainties on the densities of the transiting planets b and c are decreased by a factor of 3. Internal structure and atmospheric simulations draw a contrasting picture between HD 3167d, likely a rocky super-Earth that lost its atmosphere through photo-evaporation, and HD 3167c, a mini-Neptune that kept a substantial primordial gaseous envelope. We detect a fourth, more massive planet on a larger orbit, likely coplanar with HD 3167d-c. Dynamical simulations indeed show that the outer planetary system d-c-e was tilted, as a whole, early in the system history, when HD 3167b was still dominated by the star influence and maintained its aligned orbit. RV data and direct imaging rule out that the companion that could be responsible for the present-day architecture is still bound to the HD 3167 system. Similar global studies of multi-planet systems will tell how many share the peculiar properties of the HD 3167 system, which remains a target of choice for follow-up observations and simulations. © 2022 EDP Sciences. All rights reserved.Publisher PDFPeer reviewe

Produção fecal e digestibilidade estimada por indicadores internos comparados a coleta total

Utilizaram-se 16 novilhas (&frac34; Holandês vs. &frac14; Zebu), para as quais foi fornecida silagem de capim elefante acrescida de bagaço de mandioca como alimento único e, posteriormente, a silagem mais concentrado. Estimou-se a digestibilidade da matéria seca (MS) e da fibra em detergente neutro (FDN) além da produção fecal por meio dos indicadores internos fibra em detergente neutro indigestíveis (FDNi) e fibra em detergente ácido indigestíveis (FDAi), os quais foram comparados ao método da coleta total. A utilização da FDNi para estimar a excreção fecal e digestibilidade da MS e da FDN da silagem apresentou diferença estatística (p<0,05) em relação àquela obtida pela coleta total. A FDNi superestimou a produção fecal e subestimou a digestibilidade da MS e da FDN, o que pode ser atribuído à variabilidade inerente ao material experimental. A excreção fecal estimada pela FDNi e pela FDAi das dietas diferiu estatisticamente (p<0,05) e foi diferente, da obtida pela coleta total. A FDAi superestimou a produção fecal e subestimou a digestibilidade da MS e da FDN e a FDNi subestimou a excreção fecal e superestimou a digestibilidade da MS e da FDN, resultado diferente ao encontrado quando foi estimada a excreção fecal e avaliada a digestibilidade apenas da silagem com diferentes níveis de bagaço de mandioca no presente experimento. Mais estudos com indicadores, devem ser realizados

Bagaço de mandioca na ensilagem do capim-elefante: qualidade das silagens e digestibilidade dos nutrientes Cassava bagasse in elephant grass ensilage: quality of the silage and digestibility of the nutrients

Utilizaram-se 16 novilhas ¾ Holandês-Zebu com idade média de 15 meses e peso médio inicial de 144kg, para avaliar o efeito da adição de diferentes níveis (5; 10; 15 e 20%) de bagaço de mandioca na ensilagem do capim-elefante (Pennisetum purpureum, Schum) sobre a qualidade e a digestibilidade dos nutrientes da dieta. Os tratamentos consistiram de quatro dietas contendo, como volumoso, silagem de capim-elefante com quatro diferentes níveis de bagaço de mandioca, mais concentrado balanceado, com quatro repetições por tratamento. Avaliou-se a qualidade das silagens, os consumos de nutrientes das dietas e as digestibilidades dos nutrientes das silagens e das dietas totais. O bagaço de mandioca elevou o teor de matéria seca (MS) da silagem, preservando-a com o pH que variou de 3,85 a 4,07 e a relação N-NH3/NT de 6,2 a 7,85. Os consumos médios diários de MS e proteína bruta (PB) não diferiram entre os tratamentos (P>0,05). Os consumos médios de fibra em detergente neutro (FDN) e fibra em detergente ácido (FDA) apresentaram comportamento linear decrescente (P<0,05) com o aumento dos níveis de bagaço de mandioca. Não foi detectada diferença entre os tratamentos (P>0,05) na digestibilidade da MS (DMS), da FDN (DFDN) e da FDA (DFDA) das silagens. Os nutrientes digestíveis totais (NDT) das silagens foram semelhantes em todos os tratamentos. A digestibilidade da PB (DPB), do extrato etéreo (DEE) e dos carboidratos não-fibrosos (DCNF) das silagens decresceu linearmente (P<0,05) com o aumento do nível do bagaço de mandioca nas silagens. Constatou-se que não houve diferença (P>0,05) na DMS, DPB, DFDN, DFDA, DEE, DCNF e NDT entre as dietas experimentais. O nível de adição de 5% de bagaço de mandioca à silagem de capim-elefante é satisfatório para sua preservação, propiciando boa digestibilidade.<br>Sixteen ¾ Holstein-Zebu heifers aging 15 month-old averaging 144kg were used to evaluate the effect of the additions of different levels of cassava bagasse (5; 10; 15 and 20%) to elephant grass (Pennisetum purpureum, Schum) ensilage on the diet quality and nutrients digestibility. The treatments consisted of four diets containing, as roughage, elephant grass silage with four different levels of cassava bagasse plus balanced concentrate, with four repetitions per treatment. Silages quality, diet nutrients intake and nutrients digestibility of the silages and total diets were evaluated. Cassava bagasse increased the dry matter (DM) content, of the silages preserving them with a pH varying from 3.85 to 4.07 and N-NH3/NT ratio from 6.2 to 7.85. Daily dry matter and crude protein (CP) mean intakes did not differ among the treatments (P>0.05). Neutral detergent fiber (NDF) and acid detergent fiber (ADF) mean intakes showed a decreasing linear behavior (P<0.05) with the increase of cassava bagasse levels. There was no detected difference among the treatments (P>0.05) for DM (DMD), NDF (NDFD) and ADF digestibility (ADFD). The total digestible nutrients (TDN) of the silages were similar in all the treatments. The CP (CPD), ether extract (EED) and non-fiber carbohydrates digestibility (NFCD) of the silages decreased linearly (P<0.05) with the increase of cassava bagasse levels. There was no difference (P>0.05) in DMD, CPD, NDFD, ADFD, EED, NFCD and TDN among the experimental diets. The 5% cassava bagasse addition to its elephant grass silage was satisfactory to preservation resulting in good digestibility of the elephant grass silage

Características morfogênicas e estruturais de duas espécies de braquiária adubadas com diferentes doses de nitrogênio Morphogenetic and structural characteristics of two grasses submitted to different nitrogen doses

Objetivou-se com este estudo avaliar as características morfogênicas e estruturais de Brachiaria brizantha e B. decumbens adubados com diferentes doses de nitrogênio (N). O experimento foi realizado em casa de vegetação, com quatro doses de nitrogênio (0, 75, 150 ou 225 mg/dm³) e duas gramíneas (B. brizantha e decumbens), em um delineamento de blocos casualizados com cinco repetições. A adubação nitrogenada foi parcelada em três aplicações. A taxa de aparecimento foliar, o número total de folhas e o número de perfilhos por planta na B. decumbens foram maiores que na B. brizantha. No entanto, o filocrono, a taxa de alongamento foliar e a duração de vida da folha foram maiores na B. brizantha. A B. decumbens e a brizantha responderam de forma crescente até a dose de 190 mg/dm³ de nitrogênio para a maioria das características avaliadas. O processo de senescência destas forrageiras acelera com o aumento das doses de nitrogênio, reduzindo a duração de vida das folhas.<br>The objective of this work was to evaluate the morphogenetic and structural characteristics of Brachiaria brizantha and decumbens submitted to different nitrogen doses (N). The experiment was carried in a greenhouse. The treatments consisted of four N doses (0, 75, 150 and 225 mg/dm³ of N) and two grasses (Brachiaria brizantha and decumbens). Nitrogen fertilization was subdivided into three applications. A completely randomized block experimental design with five repetitions was used. For the morphogenetic and structural characteristics, the daily foliar structure emergence, total number of leaves and number of tillers per B. decumbens plant was higher for B. brizantha. However, for phyllochron, the daily foliar prolongation and life duration of the B. brizantha leaf were higher. B. decumbens and brizantha responded increasingly up to 190 mg/dm³ of nitrogen in relation to the majority the available characteristics. The process senescence is accelerated with increase of the nitrogen doses, reducing the life duration of leaves