title: Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates.
abstract: 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.
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Karina
authors.initials: K
authors.lastname: Calvopiña
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Klaus-Daniel
authors.initials: KD
authors.lastname: Umland
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rydzik
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Hinchliffe
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brem
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Spencer
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: School of Cellular & Molecular Medicine, University of Bristol, Bristol, United Kingdom matthewb.avison@bris.ac.uk.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Avison
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic; D020615:Stenotrophomonas maltophilia / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D010456:Peptides, Cyclic; C051231:lactivicin