The Cryle groups focuses on antibiotics: understanding how these compounds are made in nature, how we can reengineer these natural systems to produce new antibiotics as well as developing novel approaches to treat bacterial infections.

Given the importance of antibiotics for human health, our ultimate goal is to develop novel antibiotic therapies that we so badly need to deal with serious bacterial infections.

Research:

Antibiotics are one of the most important discoveries in human health. These compounds – largely derived from compounds found in nature – have enabled many aspects of modern medicine that we call upon today. However, the early success of antibiotics has led to a serious underinvestment in identifying new antibiotics and antimicrobial targets: this means that we as a society are in dire need of new antibiotics. One of the difficulties in achieving this goal is that antibiotics are often highly complex molecules and we are restricted to natural compounds or modified forms of these compounds. If we are to develop new antibiotics, we will need to reengineer the natural enzymatic machinery that produces antibiotics – and this will only be possible once we understand the how these complex enzymatic machineries work.

Thus, the Cryle group aims to understand the biosynthesis of one of the most important classes of clinically relevant antibiotics – the glycopeptide antibiotics, such as teicoplanin and vancomycin – in order to be able to reengineer this machinery and thus produce novel antibiotics. The Cryle group applies a range of techniques, including synthetic chemistry, biocatalysis, biochemistry and structural biology, to study these systems. The group also applies these techniques to develop novel antibiotic compounds and explore potential new targets for treating bacterial infections: here, with a focus on the serious bacterial pathogen Staphylococcus aureus.

Ultimately, this research will enable the development of novel antibiotic therapies as well as unlock new pathways to treat serious bacterial infections in the clinic.

Cryle Group photo
  • Characterising the mega-enzyme biosynthetic machineries that produce the many important antibiotics, with a focus on the glycopeptide antibiotics
  • Reengineering natural biosynthesis pathways to produce novel antibiotics
  • Developing new antibiotics and identifying potential new targets for antimicrobial therapies
Authors
Title
Published In

Payne JA, Schoppet M, Hansen MH, Cryle MJ.

Diversity of nature's assembly lines - recent discoveries in non-ribosomal peptide synthesis.

Mol Biosyst. 2016 Dec 20;13(1):9-22.

Ulrich V, Cryle MJ.

SNaPe: a versatile method to generate multiplexed protein fusions using synthetic linker peptides for in vitro applications.

J Pept Sci. 2017 Jan;23(1):16-27. doi: 10.1002/psc.2943. Epub 2016 Dec 2.

Ulrich V, Brieke C, Cryle MJ. 

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934.

Beilstein J Org Chem. 2016; 12: 2849–2864. Epub 2016 Dec 27. doi: 10.3762/bjoc.12.284 PMCID: PMC5238595

Brieke C, Yim G, Peschke M, Wright GD, Cryle MJ.

Catalytic promiscuity of glycopeptide N-methyltransferases enables bio-orthogonal labelling of biosynthetic intermediates.

Chem Commun (Camb). 2016 Nov 17;52(94):13679-13682.

Peschke M, Brieke C, Cryle MJ.

F-O-G Ring Formation in Glycopeptide Antibiotic Biosynthesis is Catalysed by OxyE.

Sci. Rep. 2016;6:35584. doi:10.1038/srep35584.

Ulrich V, Peschke M, Brieke C, Cryle MJ.

More than just recruitment: the X-domain influences catalysis of the first phenolic coupling reaction in A47934 biosynthesis by Cytochrome P450 StaH. Highlighted as a “Hot Article”.

Mol Biosyst. 2016 Oct 20;12(10):2992-3004. doi: 10.1039/c6mb00373g. Epub 2016 Aug 1.

Kittilä T, Mollo A, Charkoudian LK, Cryle MJ.

Have substrate, will travel: new structural data reveals the motion of carrier proteins in non-ribosomal peptide synthesis.

Angew Chem Int Ed Engl. 2016 Aug 16;55(34):9834-40. doi: 10.1002/anie.201602614. Epub 2016 Jul 20.

Peschke M, Gonsior M, Süssmuth RD, Cryle MJ.

Understanding the crucial interactions between Cytochrome P450s and non-ribosomal peptide synthetases during glycopeptide antibiotic biosynthesis.

Curr Opin Struct Biol. 2016 Dec;41:46-53. doi: 10.1016/j.sbi.2016.05.018. Epub 2016 Jun 9.

Peschke M, Haslinger K, Brieke C, Reinstein J, Cryle MJ.

Regulation of the P450 Oxygenation Cascade Involved in Glycopeptide Antibiotic Biosynthesis.

J Am Chem Soc. 2016 Jun 1;138(21):6746-53. doi: 10.1021/jacs.6b00307. Epub 2016 May 23.

Kokona B, Winesett ES, Nikolai von Krusenstiern A, Cryle MJ, Fairman R, Charkoudian LK.

Probing the selectivity of β-hydroxylation reactions in non-ribosomal peptide synthesis using analytical ultracentrifugation.

Anal Biochem. 2016 Feb 15;495:42-51. doi: 10.1016/j.ab.2015.11.011. Epub 2015 Dec 2.

Haslinger K, Cryle MJ.

Structure of OxyAtei: completing our picture of the glycopeptide antibiotic producing Cytochrome P450 cascade.

FEBS Lett. 2016 Feb;590(4):571-81. doi: 10.1002/1873-3468.12081. Epub 2016 Feb 15.

Kittilä T, Schoppet M, Cryle MJ.

Online pyrophosphate assay for analyzing adenylation domains of non-ribosomal peptide synthetases.

Chembiochem. 2016 Jan 11. doi: 10.1002/cbic.201500555. Epub 2016 Feb 23.

Brieke C, Maier T, Schröter M, Cryle MJ.

Design and synthesis of peptide inhibitor conjugates as probes of the Cytochrome P450s from glycopeptide antibiotic biosynthesis.

MedChemCommun 2016;7:132-140. doi: 10.1039/C5MD00332F. Epub: 2015 Sep 25.

Brieke C, Kratzig V, Peschke M, Cryle MJ.

Facile synthetic access to glycopeptide antibiotic precursor peptides for the investigation of Cytochrome P450 action in glycopeptide antibiotic biosynthesis.

Methods Mol Biol. 2016;1401:85-102. doi: 10.1007/978-1-4939-3375-4_6.

Kittilä T, Cryle MJ.

Capturing the structure of the substrate bond condensation domain.

Cell Chemical Biology 2016;23(3):315-316. doi: http://dx.doi.org/10.1016/j.chembiol.2016.03.003.

Brieke C, Peschke M, Haslinger K, Cryle MJ.

Sequential cyclization of glycopeptide antibiotic peptides combining an in vitro catalytic cascade of cytochrome P450 enzymes and the X-domain from peptide biosynthesis.

Angew Chem Int Ed Engl. 2015; 54(52):15715-15719. doi: 10.1002/anie.201507533.

Al Toma RS, Brieke C, Maximowitsch E, Cryle MJ, Süssmuth RD.

Structural aspects of phenylglycines, their biosynthesis and occurrence in peptide natural products.

Nat Prod Rep. 2015;32:1207-1235. doi: 10.1039/C5NP00025D. Epub 05 May 2015.

Haslinger K, Peschke M, Brieke C, Maximowitsch E, Cryle MJ.

X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis.

Nature. 2015 May 7;521(7550):105-9. doi: 10.1038/nature14141. Epub 2015 Feb 9. Recommended as being of special significance by the Faculty of 1000; Highlighted in Nature Chemical Biology.

Haslinger K, Redfield C, Cryle MJ.

Structure of the terminal PCP domain of the non-ribosomal peptide synthetase in teicoplanin biosynthesis.

Proteins. 2015 Apr;83(4):711-21. doi: 10.1002/prot.24758. Epub 2015 Feb 5.

Zhang A, Zhang T, Hall EA, Hutchinson S, Cryle MJ, Wong LL, Zhou W, Bell SG.

The crystal structure of the versatile cytochrome P450 enzyme CYP109B1 from Bacillus subtilis.

Mol Biosyst. 2015 Mar;11(3):869-81. doi: 10.1039/c4mb00665h. Epub 2015 Jan 14.

Brieke C, Kratzig V, Haslinger K, Winkler A, Cryle MJ.

Rapid access to glycopeptide antibiotic precursor peptides coupled with cytochrome P450-mediated catalysis: towards a biomimetic synthesis of glycopeptide antibiotics.

Org Biomol Chem. 2015 Feb 21;13(7):2012-21. doi: 10.1039/c4ob02452d.

Haslinger K, Maximowitsch E, Brieke C, Koch A, Cryle MJ.

Cytochrome P450 OxyBtei catalyzes the first phenolic coupling step in teicoplanin biosynthesis.

Chembiochem. 2014 Dec 15;15(18):2719-28. doi: 10.1002/cbic.201402441. Epub 2014 Oct 30.

Haslinger K, Brieke C, Uhlmann S, Sieverling L, Süssmuth RD, Cryle MJ.

The structure of a transient complex of a nonribosomal peptide synthetase and a cytochrome P450 monooxygenase.

Angew Chem Int Ed Engl. 2014 Aug 4;53(32):8518-22. doi: 10.1002/anie.201404977. Epub 2014 Jul 9.

Brieke C, Cryle MJ.

A facile Fmoc solid phase synthesis strategy to access epimerization-prone biosynthetic intermediates of glycopeptide antibiotics.

Org Lett. 2014 May 2;16(9):2454-7. doi: 10.1021/ol500840f. Epub 2014 Apr 14.

Cryle MJ, Brieke C, Haslinger K.

Oxidative transformations of amino acids and peptides catalysed by cytochromes P450.

Amino Acids, Peptides and Proteins. 2013;38:1–36. doi: 10.1039/9781849737081-00001.

Maul MJ, Barends TR, Glas AF, Cryle MJ, Domratcheva T, Schneider S, Schlichting I, Carell T.

Crystal structure and mechanism of a DNA (6-4) photolyase.

Angew Chem Int Ed Engl. 2008;47(52):10076-80. doi: 10.1002/anie.200804268.

De Voss JJ, Cryle MJ.

Carbon-carbon bond cleavage by P450 systems.

The Ubiquitous Roles of Cytochrome P450 Proteins, Vol. 3 of Metal Ions in Life Sciences. 2007;397-430.

Cryle MJ, De Voss JJ.

Is the ferric hydroperoxy species responsible for sulfur oxidation in cytochrome P450s?

Angew Chem Int Ed Engl. 2006;45(48):8221-8223. doi:10.1002/anie.200603411.