Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding

Parmar, Anish and Iyer, Abhishek and Prior, Stephen H. and Lloyd, Daniel G. and Goh, Eunice and Vincent, Charlotte and Palmai-Pallag, Timea and Bachrati, Csanad and Breukink, Eefjan and Madder, Annemieke and Lakshminarayanan, Rajamani and Taylor, Edward J. and Singh, Ishwar (2017) Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding. Chemical Science . ISSN 2041-6520

Full content URL: http://dx.doi.org/10.1039/C7SC03241B

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Abstract

Abstract. Teixobactin is a highly promising antibacterial depsipeptide consisting of four D-amino acids and a rare L-allo-enduracididine
amino acid. L-allo-enduracididine is reported to be important for the highly potent antibacterial activity of teixobactin. However, it is also a
key limiting factor in the development of potent teixobactin analogues due to several synthetic challenges such as it is not commercially
available, requires a multistep synthesis, long and repititive couplings (16-30 hours). Due to all these challenges, the total synthesis of
teixobactin is laborious and low yielding (3.3%). In this work, we have identified a unique design and developed a rapid synthesis (10 min
μwave assisted coupling per amino acid, 30 min cyclisation) of several highly potent analogues of teixobactin with yields of 10-24% by
replacing the L-allo-enduracididine with commercially available non-polar residues such as leucine and isoleucine. Most importantly, the
Leu10-teixobactin and Ile10-teixobactin analogues have shown highly potent antibacterial activity against a broader panel of MRSA and
Enterococcus faecalis (VRE). Time-kill kinetics data indicate that both these compounds are superior to vancomycin against MRSA (16
times more potent). Furthermore, these synthetic analogues displayed identical antibacterial activity to natural teixobactin (MIC 0.25 μg/ml)
against MRSA ATCC 33591 despite their simpler design and ease of synthesis. Detailed NMR analyses have provided us with further
insight into the 3D structures of these important analogues. We have confirmed lipid II binding and measured the binding affinities of
individual amino acid residues of Ala10-teixobactin towards geranyl pyrophosphate (a lipid II mimic) by NMR to understand the nature and
strength of binding interactions of the amino acid residues. An antagonization assay further confirms a lipid II mediated mode of action.
Contrary to current understanding, we have shown that a cationic amino acid at position 10 is not essential for target (lipid II) binding and
potent antibacterial activity of teixobactin. We thus provide strong evidence contrary to the many assumptions made about the mechanism of
action of this exciting new antibiotic. Introduction of a non-cationic residue at position 10 allows for tremendous diversification in terms of
the design and synthesis of highly potent teixobactin analogues and lays the foundations for the development of teixobactin analogues as
new drug-like molecules to target MRSA and Mycobacterium tuberculosis.

Keywords:antibacterial, peptide, antimicrobial
Subjects:C Biological Sciences > C720 Biological Chemistry
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
C Biological Sciences > C500 Microbiology
Divisions:College of Science > School of Pharmacy
ID Code:28993
Deposited On:06 Oct 2017 08:29

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