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Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance. From a new species of β-proteobacteria, an antibiotic called teixobactin that does not generate resistance has been characterized; the antibiotic has two different lipid targets in different bacterial cell wall synthesis components, which may explain why resistance was not observed. Teixobactin, a robust dual-action antibiotic Most antibiotics in clinical use were discovered by screening cultivable soil microorganisms, a much depleted resource that has not been adequately replaced by synthetic approaches. Hence the widespread alarm at the spread of antibiotic resistance. This paper presents some welcome good news, in the form of the isolation and characterization of a new antibiotic active against a range of bacterial pathogens including Staphylococcus aureus , and apparently untroubled by the evolution of resistance. Kim Lewis and colleagues use a recently developed system for in situ cultivation of previously uncultured soil bacteria and identify a β-proteobacterium, Eleftheria terrae sp. that produces a depsipeptide they call teixobactin. Teixobactin is active in vivo and separately targets precursors in the biosynthetic pathways for each of two major components of the bacterial cell wall, peptidoglycan and teichoic acid. Screens for mutants resistant teixobactin were negative, perhaps a consequence of this novel two-target mechanism.

Nature 517, 455–459 (2015); doi:10.1038/nature14098 In Fig. 3d of this Article, the ‘2:1’ and ‘1:1’ labels at the bottom of the panel were inadvertently switched during the production process; this figure has now been corrected in the online versions of the paper.

Previous studies on general parenting have demonstrated the relevance of strict parenting within a supportive social context for a variety of adolescent behaviors, such as alcohol use. Yet, alcohol-specific parenting practices are generally examined as separate predictors of adolescents’ drinking behavior. The present study examined different developmental profiles of alcohol-specific parenting (rule-setting, quality and frequency of communication about alcohol use) and how these patterns relate to the initiation and growth of adolescents’ drinking. A longitudinal sample of 883 adolescents (47 % female) including four measurements (between ages 12 and 16) was used. Latent class growth analysis revealed that five classes of parenting could be distinguished. Communication about alcohol appeared to be fairly stable over time in all parenting classes, whereas the level of rule-setting declined in all subgroups of parents as adolescents grow older. Strict rule-setting in combination with a high quality and frequency of communication was associated with the lowest amount of drinking; parents scoring low on all these behaviors show to be related to the highest amount of drinking. This study showed that alcohol-specific rule-setting is most effective when it coincides with a good quality and frequency of communication about alcohol use. This indicates that alcohol-specific parenting behaviors should be taken into account as an alcohol-specific parenting context, rather than single parenting practices. Therefore, parent-based alcohol interventions should not only encourage strict rule setting, the way parents communicate with their child about alcohol is also of major importance.

Clouds and aerosols contribute the largest uncertainty to current estimates and interpretations of the Earth’s changing energy budget. Here we use a new-generation large-domain large-eddy model, ICON-LEM (ICOsahedral Non-hydrostatic Large Eddy Model), to simulate the response of clouds to realistic anthropogenic perturbations in aerosols serving as cloud condensation nuclei (CCN). The novelty compared to previous studies is that (i) the LEM is run in weather prediction mode and with fully interactive land surface over a large domain and (ii) a large range of data from various sources are used for the detection and attribution. The aerosol perturbation was chosen as peak-aerosol conditions over Europe in 1985, with more than fivefold more sulfate than in 2013. Observational data from various satellite and ground-based remote sensing instruments are used, aiming at the detection and attribution of this response. The simulation was run for a selected day (2 May 2013) in which a large variety of cloud regimes was present over the selected domain of central Europe. It is first demonstrated that the aerosol fields used in the model are consistent with corresponding satellite aerosol optical depth retrievals for both 1985 (perturbed) and 2013 (reference) conditions. In comparison to retrievals from ground-based lidar for 2013, CCN profiles for the reference conditions were consistent with the observations, while the ones for the 1985 conditions were not. Similarly, the detection and attribution process was successful for droplet number concentrations: the ones simulated for the 2013 conditions were consistent with satellite as well as new ground-based lidar retrievals, while the ones for the 1985 conditions were outside the observational range. For other cloud quantities, including cloud fraction, liquid water path, cloud base altitude and cloud lifetime, the aerosol response was small compared to their natural variability. Also, large uncertainties in satellite and ground-based observations make the detection and attribution difficult for these quantities. An exception to this is the fact that at a large liquid water path value (LWP > 200 g m−2), the control simulation matches the observations, while the perturbed one shows an LWP which is too large. The model simulations allowed for quantifying the radiative forcing due to aerosol–cloud interactions, as well as the adjustments to this forcing. The latter were small compared to the variability and showed overall a small positive radiative effect. The overall effective radiative forcing (ERF) due to aerosol–cloud interactions (ERFaci) in the simulation was dominated thus by the Twomey effect and yielded for this day, region and aerosol perturbation −2.6 W m−2. Using general circulation models to scale this to a global-mean present-day vs. pre-industrial ERFaci yields a global ERFaci of −0.8 W m−2.

Intellectual disability (ID) affects 2-3% of the population. In the past, many genetic causes of ID remained unidentified due to its vast heterogeneity. Recently, whole exome sequencing (WES) studies have shown that de novo variants underlie a significant portion of sporadic cases of ID. Applying WES to patients with ID or global developmental delay at different centers, we identified three individuals with distinct de novo variants in HIVEP2 (human immunodeficiency virus type I enhancer binding protein), which belongs to a family of zinc-finger-containing transcriptional proteins involved in growth and development. Two of the variants were nonsense changes, and one was a 1 bp deletion resulting in a premature stop codon that was reported previously without clinical detail. In silico prediction programs suggest loss-of-function in the mutated allele leading to haploinsufficiency as a putative mechanism in all three individuals. All three patients presented with moderate-to-severe ID, minimal structural brain anomalies, hypotonia, and mild dysmorphic features. Growth parameters were in the normal range except for borderline microcephaly at birth in one patient. Two of the patients exhibited behavioral anomalies including hyperactivity and aggression. Published functional data suggest a neurodevelopmental role for HIVEP2, and several of the genes regulated by HIVEP2 are implicated in brain development, for example, SSTR-2, c-Myc, and genes of the NF-κB pathway. In addition, HIVEP2-knockout mice exhibit several working memory deficits, increased anxiety, and hyperactivity. On the basis of the genotype-phenotype correlation and existing functional data, we propose HIVEP2 as a causative ID gene.

To test whether baseline levels of the factors accountable for the impact of the Prevention of Alcohol use in Students (PAS) intervention (self-control, perceived rules about alcohol and parental attitudes about alcohol), moderate the effect of the intervention. A cluster randomized trial including 3,490 Dutch early adolescents ( M age = 12.66, SD  = 0.49) and their parents randomized over four conditions: 1) parent intervention, 2) student intervention, 3) combined intervention and 4) control group. Moderators at baseline were used to examine the differential effects of the interventions on onset of (heavy) weekly drinking at 34-month follow-up. The combined intervention was only effective in preventing weekly drinking among those adolescents who reported to have lower self-control and more lenient parents at baseline. No differential effect was found for the onset of heavy weekly drinking. No moderating roles of self-control and lenient parenting were found for the separate student and parent interventions regarding the onset of drinking. The combined intervention is more effective among adolescents with low-self control and lenient parents at baseline, both factors that were a specific target of the intervention. The relevance of targeting self-control in adolescents and restrictive parenting is underlined.