Toward Structure-inspired Design and Development of New Antibacterial Drugs
Martin Caffrey, Membrane Structural and Functional Biology Group, Trinity College Dublin, Ireland
Lipoprotein maturation represents a possible Achilles’ heel common to all bacteria that should be
exploited for antibiotic development. With functions that include cell envelope stabilization, signal
transduction, catalysis, transport, and host interactions, lipoproteins play vital roles in bacterial
physiology, pathogenicity, and antibiotic resistance. Lipoproteins achieve functional maturity
through the sequential action of three membrane enzymes, essential in many pathogens. Having
active sites at the membrane surface, antibiotic access is less restricted and efflux-mediated
resistance is less of an issue. They represent attractive antibiotic targets. Targeting this posttranslational
modification pathway affords the possibility of developing therapeutics that are hard to
circumvent and that inactivate many lipoproteins without consequence for host cells. The drug
discovery route under investigation in my group seeks to benefit from high-resolution structures of
the three enzymes. These are being pursued using macromolecular X-ray crystallography and, more
recently, by cryo-electron microscopy. In my presentation, I will describe a cross-disciplinary
programme employing state-of-the-art materials and methods in synthesis, protein production,
functional and biophysical characterisation, crystallisation, crystallography, and cryo-electron
microscopy, to establish structures of the enzymes and their complexes with insights into catalytic
mechanism, specificity, and drug design. Our research efforts are partly in response to the urgent
global need for new and effective antibiotics.