Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins.
Beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBP...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2007
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| _version_ | 1797096536117608448 |
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| author | Macheboeuf, P Fischer, D Brown, T Zervosen, A Luxen, A Joris, B Dessen, A Schofield, C |
| author_facet | Macheboeuf, P Fischer, D Brown, T Zervosen, A Luxen, A Joris, B Dessen, A Schofield, C |
| author_sort | Macheboeuf, P |
| collection | OXFORD |
| description | Beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid beta-lactam inhibition. Lactivicin (LTV; 1) contains separate cycloserine and gamma-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam. Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against beta-lactam-resistant bacteria. |
| first_indexed | 2024-03-07T04:43:14Z |
| format | Journal article |
| id | oxford-uuid:d25c8e61-dfdc-46f4-87d8-a03bf43c5961 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:43:14Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:d25c8e61-dfdc-46f4-87d8-a03bf43c59612022-03-27T08:03:23ZStructural and mechanistic basis of penicillin-binding protein inhibition by lactivicins.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d25c8e61-dfdc-46f4-87d8-a03bf43c5961EnglishSymplectic Elements at Oxford2007Macheboeuf, PFischer, DBrown, TZervosen, ALuxen, AJoris, BDessen, ASchofield, CBeta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid beta-lactam inhibition. Lactivicin (LTV; 1) contains separate cycloserine and gamma-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam. Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against beta-lactam-resistant bacteria. |
| spellingShingle | Macheboeuf, P Fischer, D Brown, T Zervosen, A Luxen, A Joris, B Dessen, A Schofield, C Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. |
| title | Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. |
| title_full | Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. |
| title_fullStr | Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. |
| title_full_unstemmed | Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. |
| title_short | Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins. |
| title_sort | structural and mechanistic basis of penicillin binding protein inhibition by lactivicins |
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