Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates.
Acetamido derivatives of the naturally antibacterial non-β-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by β-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Microbiology
2016
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| _version_ | 1797103562549886976 |
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| author | Calvopiña, K Umland, K Rydzik, A Hinchliffe, P Brem, J Spencer, J Schofield, C Avison, M |
| author_facet | Calvopiña, K Umland, K Rydzik, A Hinchliffe, P Brem, J Spencer, J Schofield, C Avison, M |
| author_sort | Calvopiña, K |
| collection | OXFORD |
| description | Acetamido derivatives of the naturally antibacterial non-β-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by β-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of the LTV lactone with a catechol-type siderophore increases potency 1,000-fold against Stenotrophomonas maltophilia, a species renowned for its insusceptibility to antimicrobials. The MIC90 of modified lactone compound 17 (LTV17) against a global collection of extensively drug-resistant clinical S. maltophilia isolates was 0.063 μg · ml(-1) Sideromimic modification does not reduce the ability of LTVs to induce production of the L1 and L2 β-lactamases in S. maltophilia and does not reduce the rate at which LTVs are hydrolyzed by L1 or L2. We conclude, therefore, that lactivicin modification with a siderophore known to be preferentially used by S. maltophilia substantially increases penetration via siderophore uptake. LTV17 has the potential to be developed as a novel antimicrobial for treatment of infections by S. maltophilia More generally, our work shows that sideromimic modification in a species-targeted manner might prove useful for the development of narrow-spectrum antimicrobials that have reduced collateral effects. |
| first_indexed | 2024-03-07T06:21:51Z |
| format | Journal article |
| id | oxford-uuid:f2f93c28-4afd-4737-848f-16b967b57fcf |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:21:51Z |
| publishDate | 2016 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | oxford-uuid:f2f93c28-4afd-4737-848f-16b967b57fcf2022-03-27T12:08:16ZSideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f2f93c28-4afd-4737-848f-16b967b57fcfEnglishSymplectic Elements at OxfordAmerican Society for Microbiology2016Calvopiña, KUmland, KRydzik, AHinchliffe, PBrem, JSpencer, JSchofield, CAvison, MAcetamido derivatives of the naturally antibacterial non-β-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by β-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of the LTV lactone with a catechol-type siderophore increases potency 1,000-fold against Stenotrophomonas maltophilia, a species renowned for its insusceptibility to antimicrobials. The MIC90 of modified lactone compound 17 (LTV17) against a global collection of extensively drug-resistant clinical S. maltophilia isolates was 0.063 μg · ml(-1) Sideromimic modification does not reduce the ability of LTVs to induce production of the L1 and L2 β-lactamases in S. maltophilia and does not reduce the rate at which LTVs are hydrolyzed by L1 or L2. We conclude, therefore, that lactivicin modification with a siderophore known to be preferentially used by S. maltophilia substantially increases penetration via siderophore uptake. LTV17 has the potential to be developed as a novel antimicrobial for treatment of infections by S. maltophilia More generally, our work shows that sideromimic modification in a species-targeted manner might prove useful for the development of narrow-spectrum antimicrobials that have reduced collateral effects. |
| spellingShingle | Calvopiña, K Umland, K Rydzik, A Hinchliffe, P Brem, J Spencer, J Schofield, C Avison, M Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates. |
| title | Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates. |
| title_full | Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates. |
| title_fullStr | Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates. |
| title_full_unstemmed | Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates. |
| title_short | Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates. |
| title_sort | sideromimic modification of lactivicin dramatically increases potency against extensively drug resistant stenotrophomonas maltophilia clinical isolates |
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