Using structural biology, biochemistry, and microbiology to study the molecular mechanisms by which Gram-negative bacteria build their outer membranes and protect themselves against antibiotics.
The Gram-negative bacterial cell envelope.
Antimicrobial resistant (AMR) micro-organisms cause a major global threat to modern medicine. Gram-negative are particularly difficult to treat, in part because their outer membrane (OM) acts as a barrier against antibiotics. Therefore, it is critical to understand how bacteria build and maintain their OM, potentially allowing for novel therapeutic approaches that disrupt this barrier.
The Gram-negative bacterial cell envelope consists of an inner membrane (IM) and an OM separated by an aqueous periplasmic space. To build and maintain this OM, bacteria must transport lipids and hydrophobic proteins across the aqueous periplasm. Membrane components (such as proteins, phospholipids and lipopolysaccharides) are transported via protein pathways that form shuttles or direct bridges between the IM and OM. We use a combination of structural biology, biochemistry and bacterial genetics to investigate the function of these transport systems.
2025
Phospholipid Transport Across the Bacterial Periplasm Through the Envelope-spanning Bridge YhdP
Cooper, B.F., Clark, R., Kudhail, A., Dunn, D., Tian, Q., Bhabha, G., Ekiert, D.C., Khalid, S., Isom, G.
J Mol Biol. – 437(2):168891.
2020
Structure of bacterial phospholipid transporter MlaFEDB with substrate bound.
Coudray, N.,* Isom, G.L.,* MacRae, M.R.,* Saiduddin,M.N., Bhabha, G. and Ekiert, D.C.
eLife – 9: e62518
2020
LetB Structure Reveals a Tunnel for Lipid Transport across the Bacterial Envelope
Isom, G.L.,* Coudray, N.,* MacRae, M.R., McManus, C.T., Ekiert, D.C. and Bhabha, G.
Cell – 181(3): 653-664
2017
MCE domain proteins: conserved inner membrane lipid-binding proteins required for outer membrane homeostasis
Isom, G.L., Davies, N.J., Chong, Z.S., Bryant, J.A., Jamshad, M., Sharif, M., Cunningham, A.F., Knowles, T.J., Chng, SS., Cole, J.A. and Henderson, I.R.
Scientific Reports – 7(1): 8608
2017
Architectures of lipid transport systems for the bacterial outer membrane.
Ekiert, D.C., Bhabha, G., Isom, G.L., Greenan, G., Ovchinnikov, S., Henderson, I.R., Cox, J.S. and Vale, R.D.
Cell – 169(2): 273-285