Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates

Karina Calvopiña, Klaus-Daniel Umland, Anna M Rydzik, Philip Hinchliffe, Jürgen Brem, Jim Spencer, Christopher J Schofield, Matthew B Avison

Research output: Contribution to journalArticle (Academic Journal)

7 Citations (Scopus)
135 Downloads (Pure)

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 languageEnglish
Pages (from-to)4170-4175
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number7
Early online date2 May 2016
DOIs
Publication statusPublished - Jul 2016

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