Identification of β-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 β-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents

Seeding uniformity for vacuum precision seeders Uniformidade de semeaduras para semeadeiras de precisão a vácuo

The performance of three vacuum precision seeders was investigated in a field study. Seeding uniformity was determined in three different within-row distances: 14, 18 and 21 cm. The seeders were operated at 1.8, 3.6, 5.4 and 7.2 km h-1. Successive seed spacing along of 3 m of row was measured in three replications on each row. For evaluating the seeding uniformity of seeders, seed spacings were analyzed using the methods (MISS, MULT, QFI and PREC). There were no differences between seeders. For P < 0.01, operating speed affected MISS and QFI values, and the within-row seed spacing affected MULT and PREC values. The best operating speed was 1.8 km h-1 because of the highest QFI value (88.5%). There was no difference between 1.8 and 3.6 km h-1. The speeds, 1.8 and 3.6 km h-1, were different from 5.4 and 7.2 km h-1. The best within-row distance was 18 cm because the QFI value was higher than those of 14 and 20 cm, 86.9%, 82.0% and 81.8%, respectively. The best PREC value was obtained for 21 cm within-row distance (17.4%). PREC values were acceptable for precision seeding in all trials.<br>O comportamento de três semeadeiras de precisão a vácuo foi investigado em um estudo de campo. A uniformidade de semeadura foi determinada para três distâncias de entrelinha: 14, 18 e 21 cm. As semeadeiras operaram nas velocidades de 1,8; 3,6; 5,4 e 7,2 km h-1. O espaçamento entre sementes sucessivas foi feito ao longo de 3 m de linha, com três repetições em cada linha. Para avaliar a uniformidade, os espaçamentos entre sementes foram analisados usando os métodos (MISS, MULT, QFI e PREC) e nos resultados não foi achada diferença entre semeadeiras. Para P < 0,001 a velocidade de operação afetou MISS e QFI e o espaçamento entre linhas afetou MULT e PREC. A melhor velocidade de operação foi de 1,8 km h-1 devido ao seu mais alto valor de QFI (88,5%). Não houve diferença entre as velocidades de 1,8 e 3,6 km h-1, mas elas foram diferentes das velocidades 5,4 e 7,2 km h-1. A melhor distância entre linhas foi de 18 cm, pois seu QFI foi maior em relação à 14 e 20 cm, 86,9%, 82,0% e 81,8%, respectivamente. O melhor PREC foi obtido para 21 cm de entrelinha (17,4) e os valores de PREC foram aceitáveis para todos experimentos

A surface plasmon resonance-based solution affinity assay for heparan sulfate-binding proteins

A surface plasmon resonance-based solution affinity assay is described for measuring the Kd of binding of heparin/heparan sulfate-binding proteins with a variety of ligands. The assay involves the passage of a pre-equilibrated solution of protein and ligand over a sensor chip onto which heparin has been immobilised. Heparin sensor chips prepared by four different methods, including biotin–streptavidin affinity capture and direct covalent attachment to the chip surface, were successfully used in the assay and gave similar Kd values. The assay is applicable to a wide variety of heparin/HS-binding proteins of diverse structure and function (e.g., FGF-1, FGF-2, VEGF, IL-8, MCP-2, ATIII, PF4) and to ligands of varying molecular weight and degree of sulfation (e.g., heparin, PI-88, sucrose octasulfate, naphthalene trisulfonate) and is thus well suited for the rapid screening of ligands in drug discovery applications