"Our lab uses the tools of organic synthesis, genetic engineering and molecular biology to study novel enzymatic processes, antimicrobial resistance mechanisms and the mechanism of action of antimicrobial and anticancer peptides."Dr Stephen Cochrane
Lecturer in Organic Chemistry
Office: DKB 02.004 I Tel: +44 (0)28 9097 4389 I @Cochrane_Lab
Stephen graduated with an MSci in Chemistry from Queen's University Belfast in 2010. He then moved to the University of Alberta in Canada to undertake a PhD in organic chemistry with Professor John Vederas. His research focused on structural and mechanistic studies on antimicrobial lipopeptides, namely the tridecaptins, which show strong activity against multidrug resistant Gram-negative bacteria. In 2016 he was awarded a Sir Henry Wellcome Postdoctoral Fellowship to study the transport of lipid-linked carbohydrates across bacterial cell membranes at the University of Oxford with Professor Benjamin G. Davis. During this time he also worked on the synthesis of new tunicamycin analogues with reduced cytotoxicity. In 2017 Stephen was appointed as a Lecturer in Organic Chemistry at Queen's University Belfast.
Research
Novel Syntheses of Antimicrobial Peptides
Antimicrobial peptides produced by bacteria are becoming increasingly important in the fight against multidrug resistance. These compounds typically target bacterial cell membranes, and as it is difficult for bacteria to reorganize their membranes, resistance development is often limited. Our lab develops new synthetic methods to access novel antimicrobial peptides, allowing their antimicrobial and/or anticancer activities to be explored. We also use molecular biology and bioinformatics to identify the mechanism by which they exert their therapeutic effect.
The Study of Antimicrobial Peptide Resistance Mechanisms
Although resistance mechanisms against antimicrobial peptides are limited, they are not resistance-proof. Understanding resistance mechanisms against antibiotics is important, as it can allow us to circumvent these mechanisms and restore activity. In the Cochrane Lab, we are particularly interested in enzymes that sequester the activity of antimicrobial peptides by chemically capping basic residues. Using a combination of organic synthesis, molecular biology and bioinformatics, we identify and study these enzymes, with the goal of determining their mechanism of action, as well as designing inhibitors to block their activity.
Mechanistic Studies on Glycolipid Flippases
Bacteria produce several polysaccharides that are essential to their structural integrity, including peptidoglycan and lipopolysaccharide. As the enzymes and intermediates involved in their biosynthesis are unique to bacteria, they are excellent antibiotic targets. In particular, the mechanism by which glycolipids are transported across cell membranes (by flippases) is poorly understood. Our lab uses the tools of organic synthesis to prepare glycolipid substrates for probing the mechanism of action of these enzymes, as well as using structure-activity relationship studies to guide inhibitor design, with the goal of developing new antibiotic candidates.
Recent Publications
The Antimicrobial Lipopeptide Tridecaptin A1 Selectively Binds to Gram-Negative Lipid II
S. A. Cochrane, B. Findlay, A. Bakhtiary, J. Z. Acedo, E. M. Rodriguez-Lopez, P. Mercier and J. C. Vederas, Proc. Natl. Acad. Sci. USA 2016, 113(41), 11561 - 11566. View
Lipopeptides from Bacillus and Paenibacillus spp.: A Gold Mine of Antibiotic Candidates
S. A. Cochrane and J. C. Vederas, Med. Res. Rev. 2016, 36(1), 4 - 31. View
Synthesis of Tridecaptin-Antibiotic Conjugates with in Vivo Activity Against Gram-Negative Bacteria
S. A. Cochrane, X. Li, S. He, M. Yu, M. Wu and J. C. Vederas, J. Med. Chem. 2015, 58(24), 9779 - 9785. View
Total Synthesis and Stereochemical Assignment of the Antimicrobial Lipopeptide Cerexin A1
S. A. Cochrane, R. R. Surgenor, K. M. W. Khey and J. C. Vederas, Org. Lett. 2015,17(21), 5428 - 5431. View
Studies on Tridecaptin B1, a New Tridecaptin Analogue with Activity Against Multidrug Resistant Gram-Negative Bacteria
S. A. Cochrane, C. T. Lohans, M. J. van Belkum, M. Bels and J. C. Vederas, Org. Biomol. Chem. 2015,13(21), 6073 - 6081. View
Molecular Cloning and Characterization of Drimenol Synthase from Valerian (Valeriana officinalis)
M. Kwon, S. A. Cochrane, J. C. Vederas and D-K Ro, FEBS Lett. 2014,588(24), 4597 - 4603. View
Unacylated Tridecaptin A1 Acts as an Effective Sensitizer of Gram-Negative Bacteria to Other Antibiotics
S. A. Cochrane and J. C. Vederas, Int. J. Antimicrob. Agents 2014, 44(6), 493 - 499. View
Key Residues in Octyl-tridecaptin A1 Analogs Linked to Stable Secondary Structure in the Membrane
S. A. Cochrane, B. Findlay, J. C. Vederas and E. S. Ratemi, ChemBioChem 2014, 15(9), 1295 - 1299. View
Synthesis and Structure-Activity Relationship Studies of N- Terminal Analogues of the Antimicrobial Peptide Tridecaptin A1
S. A. Cochrane, C. T. Lohans, J. R. Brandelli, G. Mulvey, G. D. Armstrong and J. C. Vederas, J. Med. Chem. 2014, 57(3), 1127 - 1131. View
Biochemical, Structural and Genetic Characterization of Tridecaptin A1, an Antagonist of Campylobacter jejuni
C. T. Lohans, M. J. van Belkum, S. A. Cochrane, Z. Huang, C. S. Sit, L. M. McMullen and J. C. Vederas, ChemBioChem 2014, 15(2), 243 - 249. View
Investigation of the Ring-Closing Metathesis of Peptides in Water
S. A. Cochrane, Z. Huang and J. C. Vederas, Org. Biomol. Chem. 2013, 11(4), 630 - 639. View
Solid Supported Chemical Synthesis of Both Components of the Lantibiotic Lacticin 3147
W. Liu, A. S. H. Chan, H. Liu, S. A. Cochrane and J. C. Vederas, J. Am. Chem. Soc. 2011, 133(36), 14216 - 14219. View