Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential beta-lactamase stable beta-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.Peer reviewe

A century of trends in adult human height

Abstract Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries

Noisy-le-Sec, gentrification under pressure. Report from Paris's supposed gentrification front line

International audienc

Noisy-le-Sec, gentrification under pressure. Report from Paris's supposed gentrification front line

International audienc

Social and Digital Resources: The Hindered Information Practices of Cancer Patients

International audienceThis chapter focuses on hindered informational practices by presenting, on the one hand, the constraints that patients face in mobilizing their close circle of family and friends in the context of the disease, and, on the other hand, the difficulties they encounter in obtaining information through the Internet. It relies on a survey using semi‐structured interviews conducted between 2010 and 2014 with approximately 60 cancer patients with various socio‐demographic characteristics. In terms of information retrieval, a distinction can be made between social resources and digital resources. Three categories of family members and friends have the possibility of transmitting information of different kinds to the patient: neophyte family members and friends; initiated family members and friends; and professional family members and friends. The Internet offers different forms of communication: patients can choose either to consult information only or to participate in discussions by asking questions, formulating answers or reacting to comments