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

Diastereoselective Hydroxymethylation of Cyclic N-tert-Butanesulfinylketimines Using Methoxymethanol as Formaldehyde Source

A stable and easy-to-handle source of anhydrous monomeric formaldehyde is used

Stereodivergent Synthesis of Pseudotabersonine Alkaloids

International audienc

Diastereoselective Hydroxymethylation of Cyclic <i>N</i>-<i>tert</i>-Butanesulfinylketimines Using Methoxymethanol as Formaldehyde Source

Hydroxymethylation of cyclic <i>tert</i>-butanesulfinylketimine-derived lithium enamides with methoxymethanol proceeds with excellent diastereoselectivity (99:1 dr). Methoxymethanol is a stable and easy-to-handle source of anhydrous monomeric formaldehyde in the reaction with lithium enamides. Cyclic α-hydroxymethyl ketimines undergo highly diastereoselective reduction to <i>syn</i>- or <i>anti</i>-1,3-amino alcohols

Diastereoselective Hydroxymethylation of Cyclic <i>N</i>-<i>tert</i>-Butanesulfinylketimines Using Methoxymethanol as Formaldehyde Source

Hydroxymethylation of cyclic <i>tert</i>-butanesulfinylketimine-derived lithium enamides with methoxymethanol proceeds with excellent diastereoselectivity (99:1 dr). Methoxymethanol is a stable and easy-to-handle source of anhydrous monomeric formaldehyde in the reaction with lithium enamides. Cyclic α-hydroxymethyl ketimines undergo highly diastereoselective reduction to <i>syn</i>- or <i>anti</i>-1,3-amino alcohols

A relationship between metabolic rate and risk-taking behaviour is revealed during hypoxia in juvenile European sea bass

&lt;p&gt;1. Inter-individual variation in metabolic rate exists in a wide range of taxa. While this variation appears to be linked to numerous aspects of animal behaviour and personality, the ecological relevance of these relationships is not understood. The behavioural response of individual fish to acute aquatic hypoxia, for example, could be related to metabolic rate via influences on oxygen demand or the willingness to take risks. Individuals with higher metabolic rates could show greater hypoxia-associated increases in activity that could allow them to locate areas with increased oxygen availability but that also make them susceptible to predation. Any relationship between metabolic rate and risk-taking behaviour among individual fish could therefore be modulated by environmental oxygen levels, perhaps becoming stronger as oxygen availability declines.&lt;/p&gt; &lt;p&gt;2. We measured spontaneous swimming activity as an index of risk-taking by juvenile European sea bass in normoxia, moderate hypoxia (40% air saturation) and severe hypoxia (20% air saturation) after being startled by a predator model. All fish were also separately measured for routine metabolic rate by measuring oxygen uptake.&lt;/p&gt; &lt;p&gt;3. In hypoxia, fish re-emerged from cover sooner after a simulated attack and were generally more active than when the same fish were startled in normoxia. In addition, individual activity and risk-taking in severe hypoxia were positively correlated with metabolic rate. Aquatic surface respiration was a major contributor towards increased activity in hypoxia and was positively related to metabolic rate during severe hypoxia. There were no relationships between risk-taking and metabolic rate in moderate hypoxia or normoxia.&lt;/p&gt; &lt;p&gt;4. Relative measures of risk-taking among individual fish were not consistent among oxygen levels, further suggesting that individuals differ in sensitivity to hypoxia and the degree to which this environmental stressor affects risk-taking behaviour.&lt;/p&gt; &lt;p&gt;5. These results suggest that fish with relatively high metabolic rates become more active during acute hypoxia, possibly leading to increased susceptibility to predation in response to differences in metabolic demand. In addition, the relationship between metabolic rate and risk-taking may only be observable during exposure to a physiological stressor or such a stressor may strengthen any relationships observable under more benign conditions.&lt;/p&gt

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

Environmental influence on commercial fishery landings of small pelagic fish in Portugal

Small pelagic fishes are particularly abundant in areas with high environmental variability (zones of coastal upwelling and areas of tidal mixing and river discharge), and because of this, their abundance suffers large inter-annual and inter-decadal fluctuations. In Portugal, the most important species in terms of landings are European sardine, Atlantic horse mackerel and Atlantic chub mackerel. Small pelagic fish landings account for 62.8 % of the total fish biomass and represent 32.7 % of the economical value of all catches. We have investigated trends in landings of these small pelagic fishes and detected the effects of environmental factors in this fishery. In order to explain the variability of landings of small pelagic fishes, we have used official landings (1965-2012) for trawling and purse seine fisheries and applied generalized linear models, using the North Atlantic Oscillation index (NAO) (annual and winter NAO index), sea surface temperature (SST), wind data (strength and North-South and East-West wind components) and rainfall, as explanatory variables. Regression analysis was used to describe the relationship between landings and SST. The models explained between 50.16 and 51.07 % of the variability of the LPUE, with the most important factors being winter NAO index, SST and wind strength. The LPUE of European sardine and Atlantic horse mackerel was negatively correlated with SST, and LPUE of Atlantic chub mackerel was positively correlated with SST. The use of landings of three important species of small pelagic fishes allowed the detection of variations in landings associated with changes in sea water temperature and NAO index