STRUCTURAL STUDIES ON METALLO BETA-LACTAMASES

Jakir Hussain Ullah

Department of Protein Structure MRC National Institute for Medical Research telephone
E-mail: j-ullah@anika.nimr.mrc.ac.uk

Metallo b-lactamases are enzymes that can inactivate almost all b-lactam antibiotics including penicillins, cephalosporins and carbepenems. Only metallo b-lactamases have activity against carbepenems. At present metallo b-lactamases have been observed in only a few species and with the exception of stenotrophomonas maltophilia and bacteroides fragilis, are non pathogenic. Recent reports have suggested the dissemination of metallo b- lactamase genes by plasmid borne methods. The spread of these genes to the bacterial population could severely compromise current antibiotic therapy. The work described here is therefore an attempt to provide detailed structural information on metallo b-lactamases to facilitate the development of novel inhibitory compounds. Stenotrophomonas maltophilia has recently emerged as a nosocomial pathogen in patients that are immuno-compromised as a result of cancer, cystic fibrosis or organ transplantation. b-lactam resistance is conferred by two chromosomally encoded enzymes, a class C serine b-lactamase (a cephalosporinase) named L2 and a class B metallo b-lactamase named L1, that are inducibly expressed. The metallo b-lactamase, L1, has been previously characterised and shown to exits as a tetramer; a form which is unique to stenotrophomonas maltophilia. This poster will describe the work carried out obtain the refined crystal structure of the metallo b-lactamase, L1, from stenotrophomonas maltophilia to 1.7A resolution.