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Phosphonate inhibit...
Phosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2
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- Palica, Katarzyna, 1992- (author)
- Uppsala universitet,Organisk kemi
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Deufel, Fritz (author)
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Skagseth, Susann (author)
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Di Santo, Paula (author)
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Andersson Rasmussen, Anna (author)
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Valkonen, Arto (author)
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Sunnerhagen, Per (author)
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Schroder Leiros, Hanna-Kirsti (author)
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Andersson, Hanna (author)
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Erdélyi, Máté (author)
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(creator_code:org_t)
- English.
- Related links:
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https://urn.kb.se/re...
Abstract
Subject headings
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- The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics, and they are increasingly disseminated worldwide. Inhibition of metallo-β-lactamases could allow the continued use of existing β-lactam antibiotics, such as pencillins and cephalosporins, whose applicability is becoming ever more limited. However, so far there are no clinically applicable inhibitors. The design, synthesis, and NDM-1, VIM-2, and GIM-1 inhibitory activities of a series of novel phosphonate-based inhibitor candidates is presented herein along with the solution NMR spectroscopic and computational identification of their NDM-1 and VIM-2 binding sites and binding modes. VIM-2 showed a higher conformational flexibility than NDM-1, complexed a larger number of phosphonate-based inhibitor candidates in more varying binding modes. This may indicate that it has a larger substrate promiscuity. Phosphonate-type transition-state mimicking inhibitors are demonstrated to be potential candidates for development into therapeutics to combating metallo-β-lactamase resistant bacteria
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
Publication and Content Type
- vet (subject category)
- ovr (subject category)
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