Targeting antibiotic resistance in <em>Neisseria</em>: Structure of a membrane bound endotoxin modifying enzyme — ASN Events
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  2. Session 6: Hot Topics
  3. Targeting antibiotic resistance in Neisseria: Structure of a membrane bound endotoxin modifying enzyme

Targeting antibiotic resistance in Neisseria: Structure of a membrane bound endotoxin modifying enzyme (#15)

Alice Vrielink 1 , Anandhi Anandan 1 , Isabel Moraes 2 3 , Charlene M. Kahler 4
  1. School of Chemistry and Biochemistry, University of Western Australia, Perth, WA, Australia
  2. Department of Life Sciences, Imperial College London, London, UK
  3. Membrane Protein Laboratory, Diamond Light Source, Didcot, UK
  4. School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia
Multidrug resistance (MDR) in Gram-negative bacteria (GNB) represents one of the most intractable problems facing modern medicine. Not only is antibiotic resistance incrementally increasing during clinical treatment of infections, but also the evolution and acquisition of new mechanisms of antibiotic resistance leads to loss of the capacity to treat infections. The rapid development of multidrug resistance in Gram-negative bacterial species, resulting in sepsis, necessitates the use of second-line drugs such as polymyxin [1]. Polymyxin is a cationic polypeptide and the structural motif of the molecule and others of this class of cationic microbial peptides (CAMPs) allows them to bind to the bacterial surface and intercalate into the outer membrane. From this location they diffuse across the periplasm and intercalate into the inner membrane, forming pores, which eventually lead to bacterial cell lysis. The initial interactions of polymyxin with the bacterial surface relies on the electrostatic interaction between the positively charged nature of the antibiotic and the negative charge on the bacterial surface generated by the phosphate groups on the lipid A of lipopolysaccharide [2].  However many of the sepsis causing bacteria, including the most recent superbug, Neisseria gonorrhoeae, which causes untreatable sexually transmitted infections, are intrinsically resistant to polymyxin. Resistance to polymyxin is determined by the action of a lipid A modifying phosphoethanolamine (PEA) transferase (LptA) which catalyses the addition of phosphoethanolamine (PEA) to the 1 and 4’ phosphates of the lipid A headgroups [3]. This effectively blocks polymyxin and other CAMPs from interaction with the bacterial surface, resulting in resistance. Currently there are no methods available to overcome this resistance mechanism and thus strategies for blocking the action of this enzyme are of considerable interest. Towards this goal we have recently determined the crystal structure of neisserial LptA. The enzyme is composed of a soluble domain containing the catalytic site and an alpha helical trans-membrane domain.  An intriguing bridging helix, connecting the two domains is positioned parallel to the membrane surface and may be partially buried in the bilayer.  A bound detergent molecule at the active site of the enzyme provides insights into the mechanism of substrate recognition and catalysis.
  1. Balaji V., Jeremiah S.S. and Baliga P.R. (2011). Indian Journal of Medical Microbiology, 29, 230-42.
  2. Velkov T., Thompson P.E., Nation R.L. and Li J. (2010). Journal of Medicinal Chemistry, 53, 1898-916.
  3. Cox A.D., Wright J.C., Li J., Hood D.W., Moxon E.R. and Richards, J.C. (2003). Journal of Bacteriology, 185, 3270-7.