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Abstract
Acetamido derivatives of the naturally antibacterial non-β-lactam Lactivicin 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 lactivicin (LTV) lactone with a catechol-type siderophore increases potency 1000-fold against Stenotrophomonas maltophilia, a species renowned for its insusceptibility to antimicrobials. The MIC90 of the modified lactone 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 L1/L2 β-lactamase production 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.
Original language | English |
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Pages (from-to) | 4170-4175 |
Number of pages | 6 |
Journal | Antimicrobial Agents and Chemotherapy |
Volume | 60 |
Issue number | 7 |
Early online date | 2 May 2016 |
DOIs | |
Publication status | Published - Jul 2016 |
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Dive into the research topics of 'Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates'. Together they form a unique fingerprint.Projects
- 2 Finished
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Link account to CHEM RB1768 (EP/M027546/1) - Bristolbridge-Nanospears
Su, B. (Principal Investigator)
11/01/16 → 10/04/16
Project: Research
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CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface
Mulholland, A. J. (Principal Investigator)
1/07/15 → 30/04/21
Project: Research