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Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria.

Abstract：

:Resistance to the last-resort antibiotic colistin is now widespread and new therapeutics are urgently required. We report the first in toto chemical synthesis and pre-clinical evaluation of octapeptins, a class of lipopeptides structurally related to colistin. The octapeptin biosynthetic cluster consisted of three non-ribosomal peptide synthetases (OctA, OctB, and OctC) that produced an amphiphilic antibiotic, octapeptin C4, which was shown to bind to and depolarize membranes. While active against multi-drug resistant (MDR) strains in vitro, octapeptin C4 displayed poor in vivo efficacy, most likely due to high plasma protein binding. Nuclear magnetic resonance solution structures, empirical structure-activity and structure-toxicity models were used to design synthetic octapeptins active against MDR and extensively drug-resistant (XDR) bacteria. The scaffold was then subtly altered to reduce plasma protein binding, while maintaining activity against MDR and XDR bacteria. In vivo efficacy was demonstrated in a murine bacteremia model with a colistin-resistant P. aeruginosa clinical isolate.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Velkov T,Gallardo-Godoy A,Swarbrick JD,Blaskovich MAT,Elliott AG,Han M,Thompson PE,Roberts KD,Huang JX,Becker B,Butler MS,Lash LH,Henriques ST,Nation RL,Sivanesan S,Sani MA,Separovic F,Mertens H,Bulach D,Seemann T,

doi

10.1016/j.chembiol.2018.01.005

subject

Has Abstract

pub_date

2018-04-19 00:00:00

pages

380-391.e5

issue

4

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(18)30005-9

journal_volume

25

pub_type

杂志文章

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