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

Tony Velkov, Alejandra Gallardo-Godoy, James D. Swarbrick, Mark A.T. Blaskovich, Alysha G. Elliott, Meiling Han, Philip E. Thompson, Kade D. Roberts, Johnny X. Huang, Bernd Becker, Mark S. Butler, Lawrence H. Lash, Sónia Troeira Henriques, Roger L. Nation, Sivashangarie Sivanesan, Marc Antoine Sani, Frances Separovic, Haydyn Mertens, Dieter Bulach, Torsten Seemann & 3 others Jeremy Owen, Jian Li, Matthew A. Cooper

Research output: Contribution to journalArticleResearchpeer-review

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. Octapeptins are colistin-like lipopeptide antibiotics with activity against multi- and extensively drug-resistant (MDR and XDR) Gram-negative bacteria. We describe the design, synthesis, and early preclinical evaluation of a novel series of octapeptins with superior activity and pharmacokinetics.

Original languageEnglish
Pages (from-to)380-391
Number of pages12
JournalCell Chemical Biology
Volume25
Issue number4
DOIs
Publication statusPublished - 19 Apr 2018

Keywords

  • Antibiotic resistance
  • Extensively drug resistance
  • in vivo
  • Infection
  • MDR
  • Novel antibiotic
  • Octapeptin
  • Pharmacokinetics
  • Polymyxin
  • Superbug
  • XDR

Cite this

Velkov, Tony ; Gallardo-Godoy, Alejandra ; Swarbrick, James D. ; Blaskovich, Mark A.T. ; Elliott, Alysha G. ; Han, Meiling ; Thompson, Philip E. ; Roberts, Kade D. ; Huang, Johnny X. ; Becker, Bernd ; Butler, Mark S. ; Lash, Lawrence H. ; Henriques, Sónia Troeira ; Nation, Roger L. ; Sivanesan, Sivashangarie ; Sani, Marc Antoine ; Separovic, Frances ; Mertens, Haydyn ; Bulach, Dieter ; Seemann, Torsten ; Owen, Jeremy ; Li, Jian ; Cooper, Matthew A. / Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria. In: Cell Chemical Biology. 2018 ; Vol. 25, No. 4. pp. 380-391.
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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. Octapeptins are colistin-like lipopeptide antibiotics with activity against multi- and extensively drug-resistant (MDR and XDR) Gram-negative bacteria. We describe the design, synthesis, and early preclinical evaluation of a novel series of octapeptins with superior activity and pharmacokinetics.",
keywords = "Antibiotic resistance, Extensively drug resistance, in vivo, Infection, MDR, Novel antibiotic, Octapeptin, Pharmacokinetics, Polymyxin, Superbug, XDR",
author = "Tony Velkov and Alejandra Gallardo-Godoy and Swarbrick, {James D.} and Blaskovich, {Mark A.T.} and Elliott, {Alysha G.} and Meiling Han and Thompson, {Philip E.} and Roberts, {Kade D.} and Huang, {Johnny X.} and Bernd Becker and Butler, {Mark S.} and Lash, {Lawrence H.} and Henriques, {S{\'o}nia Troeira} and Nation, {Roger L.} and Sivashangarie Sivanesan and Sani, {Marc Antoine} and Frances Separovic and Haydyn Mertens and Dieter Bulach and Torsten Seemann and Jeremy Owen and Jian Li and Cooper, {Matthew A.}",
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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, Owen, J, Li, J & Cooper, MA 2018, 'Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria', Cell Chemical Biology, vol. 25, no. 4, pp. 380-391. https://doi.org/10.1016/j.chembiol.2018.01.005

Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria. / Velkov, Tony; Gallardo-Godoy, Alejandra; Swarbrick, James D.; Blaskovich, Mark A.T.; Elliott, Alysha G.; Han, Meiling; Thompson, Philip E.; Roberts, Kade D.; Huang, Johnny X.; Becker, Bernd; Butler, Mark S.; Lash, Lawrence H.; Henriques, Sónia Troeira; Nation, Roger L.; Sivanesan, Sivashangarie; Sani, Marc Antoine; Separovic, Frances; Mertens, Haydyn; Bulach, Dieter; Seemann, Torsten; Owen, Jeremy; Li, Jian; Cooper, Matthew A.

In: Cell Chemical Biology, Vol. 25, No. 4, 19.04.2018, p. 380-391.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria

AU - Velkov, Tony

AU - Gallardo-Godoy, Alejandra

AU - Swarbrick, James D.

AU - Blaskovich, Mark A.T.

AU - Elliott, Alysha G.

AU - Han, Meiling

AU - Thompson, Philip E.

AU - Roberts, Kade D.

AU - Huang, Johnny X.

AU - Becker, Bernd

AU - Butler, Mark S.

AU - Lash, Lawrence H.

AU - Henriques, Sónia Troeira

AU - Nation, Roger L.

AU - Sivanesan, Sivashangarie

AU - Sani, Marc Antoine

AU - Separovic, Frances

AU - Mertens, Haydyn

AU - Bulach, Dieter

AU - Seemann, Torsten

AU - Owen, Jeremy

AU - Li, Jian

AU - Cooper, Matthew A.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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. Octapeptins are colistin-like lipopeptide antibiotics with activity against multi- and extensively drug-resistant (MDR and XDR) Gram-negative bacteria. We describe the design, synthesis, and early preclinical evaluation of a novel series of octapeptins with superior activity and pharmacokinetics.

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KW - Antibiotic resistance

KW - Extensively drug resistance

KW - in vivo

KW - Infection

KW - MDR

KW - Novel antibiotic

KW - Octapeptin

KW - Pharmacokinetics

KW - Polymyxin

KW - Superbug

KW - XDR

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U2 - 10.1016/j.chembiol.2018.01.005

DO - 10.1016/j.chembiol.2018.01.005

M3 - Article

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EP - 391

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9456

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ER -