13 research outputs found
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
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
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
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
Sustainability of deep-sea fisheries
As coastal fisheries around the world have collapsed, industrial fishing has spread seaward and deeper in pursuit of the last economically attractive concentrations of fishable biomass. For a seafood-hungry world depending on the oceans' ecosystem services, it is crucial to know whether deep-sea fisheries can be sustainable.The deep sea is by far the largest but least productive part of the oceans, although in very limited places fish biomass can be very high. Most deep-sea fishes have life histories giving them far less population resilience/productivity than shallow-water fishes, and could be fished sustainably only at very low catch rates if population resilience were the sole consideration. But like old-growth trees and great whales, their biomass makes them tempting targets while their low productivity creates strong economic incentive to liquidate their populations rather than exploiting them sustainably (Clark's Law). Many deep-sea fisheries use bottom trawls, which often have high impacts on nontarget fishes (e.g., sharks) and invertebrates (e.g., corals), and can often proceed only because they receive massive government subsidies. The combination of very low target population productivity, nonselective fishing gear, economics that favor population liquidation and a very weak regulatory regime makes deep-sea fisheries unsustainable with very few exceptions. Rather, deep-sea fisheries more closely resemble mining operations that serially eliminate fishable populations and move on.Instead of mining fish from the least-suitable places on Earth, an ecologically and economically preferable strategy would be rebuilding and sustainably fishing resilient populations in the most suitable places, namely shallower and more productive marine ecosystems that are closer to markets