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Teixobactin Analogues Reveal Enduracididine to Be Non-Essential for Highly Potent Antibacterial Cite This: Chem Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial Cite this: Chem. Sci.,2017,8,8183 activity and lipid II binding† Anish Parmar,‡a Abhishek Iyer,‡ab Stephen H. Prior,c Daniel G. Lloyd,d Eunice Tze Leng Goh,e Charlotte S. Vincent,d Timea Palmai-Pallag, d Csanad Z. Bachrati, d Eefjan Breukink,f Annemieke Madder, b Rajamani Lakshminarayanan,e Edward J. Taylord and Ishwar Singh *a 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 repetitive couplings (16–30 hours). Due to all these challenges, Creative Commons Attribution 3.0 Unported Licence. 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 mwave 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). Furthermore, these synthetic analogues displayed identical antibacterial activity to natural teixobactin (MIC 0.25 mgmLÀ1) against MRSA ATCC 33591 despite their simpler design and ease of synthesis. We have confirmed lipid II binding and measured the binding affinities of individual amino acid residues of Ala10-teixobactin This article is licensed under a towards geranyl pyrophosphate by NMR to understand the nature and strength of binding interactions. 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 Open Access Article. Published on 05 October 2017. Downloaded 9/27/2021 9:45:45 PM. strong evidence contrary to the many assumptions made about the mechanism of action of this exciting Received 25th July 2017 new antibiotic. Introduction of a non-cationic residue at position 10 allows for tremendous Accepted 4th October 2017 diversification in the design and synthesis of highly potent teixobactin analogues and lays the DOI: 10.1039/c7sc03241b foundations for the development of teixobactin analogues as new drug-like molecules to target MRSA rsc.li/chemical-science and Mycobacterium tuberculosis. aSchool of Pharmacy, University of Lincoln, JBL Building, Beevor St., Lincoln kill kinetics), lipid II and geranyl pyrophosphate binding, cytotoxicity assay. LN67DL, UK. E-mail: [email protected] See DOI: 10.1039/c7sc03241b bOrganic and Biomimetic Chemistry Research Group, Department of Organic and ‡ These authors have contributed equally to this work. The project was Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, conceived and designed by Ishwar Singh. The manuscript was written by Belgium Abhishek Iyer, Stephen H. Prior and Ishwar Singh through contributions from cSchool of Chemistry, University of Lincoln, JBL Building, Beevor St., Lincoln all authors. Anish Parmar carried out the teixobactin analogues syntheses. LN67DL, UK Stephen H. Prior was responsible for the NMR analyses. Charlotte S. Vincent, dSchool of Life Sciences, University of Lincoln, JBL Building, Beevor St., Lincoln Daniel G. Lloyd, and Edward J. Taylor have contributed to the antibacterial LN67DL, UK studies. Timea Palmai-Pallag and Csanad Z. Bachrati carried out the toxicity eSingapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 studies. Annemieke Madder was responsible for the LC-MS analyses. Eean College Road, Singapore 169857 Breukink was responsible for the syntheses and characterisation of lipid II. fDepartment of Membrane Biochemistry and Biophysics, Institute of Biomembranes, Eunice Tze Leng Goh and Rajamani Lakshminarayanan were responsible for Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands the antibacterial studies and haemolytic assay. All authors have given approval to the nal version of the manuscript. † Electronic supplementary information (ESI) available: Peptide synthesis, HPLC, LC-MS analysis, NMR spectra, microbiological data (MIC, MBC, time This journal is © The Royal Society of Chemistry 2017 Chem. Sci.,2017,8,8183–8192 | 8183 View Article Online Chemical Science Edge Article Introduction D to L leads to signicant loss in antibacterial activity. This work also dened the 3D molecular structure of seven teixobactin By 2050, antimicrobial resistance (AMR) is predicted to cause analogues whereby (1) the disordered structure of these more mortality than cancer.1 To address the challenges of AMR, analogues were found to be vital for biological activity, (2) D-Gln4 there is a continual need to develop new antibacterial is essential and (3) D-allo-Ile5 is important to maintain the 13 compounds. The recently discovered molecule teixobactin is disordered structure. 12 one such very promising antibacterial.2 Teixobactin kills Nowick et al. reported a minimum pharmacophore of bacteria such as Methicillin-resistant Staphylococcus aureus teixobactin coined lipobactin by replacing the N-terminal resi- – (MRSA) and Mycobacterium tuberculosis without detectable dues 1 5 with a dodecanoyl chain. They described that any resistance.2 In 2015, Mycobacterium tuberculosis infected 10.4 change to D-Thr8 or modi cation of con guration of any of the million individuals and was responsible for 1.5 million deaths residues in the core ring structure of teixobactin results in worldwide.3 Teixobactin kills bacteria through the inhibition of a signi cant decrease in activity. The enantiomeric Arg10-teix- cell wall synthesis.2 The development of resistance against obactin reported by them shows similar biological activity as teixobactin is predicted to be low because it targets cell wall Arg10-teixobactin. These results suggest that, in order to main- substrates from multiple biosynthetic pathways.4 Teixobactin, tain biological activity, only the relative con gurations of amino thus, does not target enzymes, but multiple bactoprenol- acids are important and not their absolute con gurations. Very coupled cell wall building blocks such as lipid II (needed for recently, Nowick et al. also reported the X-ray crystallographic peptidoglycan synthesis) and lipid III (a starting material for structure of a teixobactin analogue and described its hydro- cell wall teichoic acid synthesis) leading to inhibition of cell wall phobic interactions, as well as a hydrogen bonding cavity 14 synthesis.5 The targeting of building blocks (lipid II and lipid featuring a chloride ion. The Albericio group has reported 15 III) rather than enzymes makes it inherently more difficult for a lysine scan of Arg10-teixobactin. They concluded that the bacteria to develop resistance. The inhibition of cell wall replacement of any one of the four isoleucine residues with Creative Commons Attribution 3.0 Unported Licence. synthesis via multiple pathways results in cell wall damage, lysis lysine led to complete loss of activity. However, replacement of (due to delocalisation of autolysins, lytic enzymes) and cell the polar, non-charged residues Ser3, Gln4 and non-polar death. The aforementioned reasons make teixobactin an alanine by lysine resulted in analogues with comparable bio- outstanding molecule for antibiotic development.6 logical activities to that of Arg10-teixobactin. Wu C. et al. have Teixobactin is an undecapeptide containing four D amino reported that the guanidine of arginine or amine of lysine at position 10, Ser and the NH group of N terminal phenylalanine acids namely N-Me-D-Phe1, D-Gln4, D-allo-Ile5 and D-Thr8 (Fig. 1, 7 marked in red) and the rare L-allo-enduracididine amino acid7 are all critical for the biological activity of teixobactin 16 (Fig. 1A, marked in blue). In the past year, articles have been analogues. The replacement of the arginine or lysine at posi- published which describe the total synthesis of teixobactin,8,9 tion 10 by histidine, Ser7 by alanine (including analogue 7) and This article is licensed under a and the syntheses and biological activities of teixobactin N-methyl phenylalanine1 by N,N-dimethyl phenylalanine leads 10–12 to less active teixobactin analogues compared to the Arg - analogues. The synthesis of Arg10-teixobactin analogues was 10 11 10,12 teixobactin. Recently, we have reported the synthesis of teix- reported by us and others. Arg10-teixobactin was obtained obactin analogues by replacing L-allo-enduracididine with iso- Open Access Article. Published on 05 October 2017. Downloaded 9/27/2021 9:45:45 PM. by replacing the L-allo-enduracididine amino acid at position 10 with the structurally similar, commercially available arginine. steres such as homoarginine10-teixobactin, norarginine10- teixobactin. These analogues showed promising activity against Arg10-teixobactin showed a similar trend in terms of antibac- terial activity as teixobactin. Our previous work13 established the MRSA. However
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