University of Birmingham Rational design and synthesis of modified teixobactin analogues: Ng, Vivian; Kuehne, Sarah A; Chan, Weng DOI: 10.1002/chem.201801423 License: Other (please specify with Rights Statement) Document Version Peer reviewed version Citation for published version (Harvard): Ng, V, Kuehne, SA & Chan, W 2018, 'Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa', Chemistry: A European Journal. https://doi.org/10.1002/chem.201801423 Link to publication on Research at Birmingham portal Publisher Rights Statement: This is the peer reviewed version of the following article: Ng, V. , Kuehne, S. and Chan, W. (2018), Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa. Chem. Eur. J.. 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The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Eur. J. 10.1002/chem.201801423 Link to VoR: http://dx.doi.org/10.1002/chem.201801423 Supported by Chemistry - A European Journal 10.1002/chem.201801423 FULL PAPER Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa [a] [b] *[a] Vivian Ng, Sarah A. Kuehne and Weng C. Chan Abstract: Teixobactin, a recently discovered depsipeptide that binds demonstrated excellent bactericidal activity against methicillin- to bacterial lipid II and lipid III, provides a promising molecular resistant Staphylococcus aureus (MRSA) which is associated scaffold for the design of new antimicrobials. Herein, we describe the with a wide range of infections in both the community (e.g. synthesis and antimicrobial evaluation of systematically modified cellulitis, abscesses) and the hospital settings (e.g. bacteraemia, teixobactin analogues. The replacement of Ile11 residue with aliphatic pneumonia).[4–6] Vancomycin is currently the last line of defence isosteres, the modification of the guanidino group at residue 10 and against MRSA infections but strains with reduced susceptibility the introduction of a rigidifying residue, dehydroamino acid into the to this antibiotic have surfaced.[7–10] Teixobactin offers a potential macrocyclic ring generated useful structure-activity information. solution to this predicament since it remains effective against Extensive antimicrobial susceptibility assessment against a panel of MRSA, as well as vancomycin-intermediate S. aureus (VISA) clinically relevant Staphylococcus aureus and Propionibacterium due to its unique mode of action.[4] It has been shown to acnes led to the identification of a new lead compound, synergistically block the biosyntheses of peptidoglycan and [Arg(Me)10,Nle11]teixobactin 63, with excellent bactericidal activity teichoic acid, thereby resulting in a weakened cell wall and (MIC 2–4 μg/mL). Significantly, the antimicrobial activity of several of autolysin-mediated cell lysis.[4,11] the teixobactin analogues against the pathogenic Gram-negative Teixobactin 1 is also a potent antimicrobial against another Pseudomonas aeruginosa was ‘restored’ when combined with sub- human skin commensal, Propionibacterium acnes.[4] This Gram- MIC concentration of the outer membrane-disruptive antibiotic, positive anaerobe is commonly associated with acnes colistin. The antimicrobial effectiveness of [Tfn10,Nle11]teixobactin 66 vulgaris.[12] In recent years, however, it is increasingly (32 μg/mL)-colistin (2 μg/mL; 0.5x MIC) combination against P. recognised as an opportunistic pathogen that can cause aeruginosa PAO1 reveals, for the first time, an alternative invasive infections, especially those associated with medical therapeutic option in the treatment of Gram-negative infections. implants.[13,14] There have been several reports on the isolation of P. acnes from prosthetic joints, cardiovascular devices and ophthalmic implants.[14–18] To aggravate matters, the widespread use of antibiotics to treat acne vulgaris has led to the emergence Introduction of P. acnes strains that are resistant to numerous antibiotics, Manuscript including the macrolides, tetracycline and metronidazole.[13,19–22] Life-saving antibiotics are rapidly losing the race against the The need for novel antimicrobials is therefore more pressing development of bacterial resistance to most, if not all, antibiotics. than ever. It is hoped that teixobactin and its analogues may The resultant health and financial implications have spurred the serve as a timely solution to this clinically important pathogen. deployment of antimicrobial stewardship programmes across the globe to ensure evidence-based prescribing of antibiotics that are still effective.[1–3] Meanwhile, scientists are working hand-in- hand to tackle the resistance crisis through drug discovery and development initiatives. Natural antimicrobial peptides serve as invaluable molecular scaffolds for the development of the next generation of antimicrobial therapeutics. The recently discovered depsipeptide, teixobactin 1 (Figure 1), has great potential as a lead compound due to its favourable potency against many Structure of teixobactin and the four sites (blue) of modification Gram-positive pathogens.[4] Among them, teixobactin has Figure 1. 1 presented in this work. Teixobactin 1, comprised of a 13-membered depsipeptide Accepted [a] V. Ng, Dr W.C. Chan core and a tethered linear heptapeptide, offers multiple sites for School of Pharmacy, Centre for Biomolecular Sciences, synthetic modifications to improve its potency and efficacy. In University of Nottingham, University Park, Nottingham, U.K., NG7 2RD. less than three years since its discovery, more than a hundred E-mail: [email protected] analogues have been synthesized by various research groups in [b] Dr. S.A. Kuehne the hope of elucidating its structure-activity relationships School of Dentistry, and Institute for Microbiology and Infection, (SARs).[23–37] The biological activities of these analogues and the University of Birmingham, Birmingham, U.K., B5 7EG. different synthetic strategies reported have been comprehensively reviewed.[38,39] X-ray crystallographic, Supporting information for this article is given via a link at the end of molecular dynamic and NMR structural studies have also been the document. conducted to construct possible binding models of the native This article is protected by copyright. All rights reserved. Chemistry - A European Journal 10.1002/chem.201801423 FULL PAPER peptide and its analogues.[26,27,40] Additionally, in a recent mini- review, we provided an insight into the structural similarities of teixobactin with other lipid II inhibitors.[41] Together, these resources provide tremendous information that could aid the design of optimised analogues. Early synthetic endeavours focused primarily on the exocyclic tail and the backbone stereochemistry of the native peptide. The replacement of any D-amino acid residues with its L-counterparts