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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.
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- 2 Finished
11/01/16 → 10/04/16
1/07/15 → 30/04/21