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Infection and Immunity, June 2000, p. 3200-3209, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification of an Immunodominant ABC Transporter in Methicillin-Resistant Staphylococcus aureus Infections

James P. Burnie,1,2,* Ruth C. Matthews,1,2 Tracey Carter,1 Elaine Beaulieu,1 Michael Donohoe,1 Caroline Chapman,1 Peter Williamson,1 and Samantha J. Hodgetts1

NeuTec Pharma plc1 and Infectious Diseases Research Group, University of Manchester,2 Central Manchester Healthcare Trust, Manchester M13 9WL, United Kingdom

Received 25 December 1999/Returned for modification 15 February 2000/Accepted 10 March 2000

Immunoblotting sera from 26 patients with septicemia due to an epidemic strain of methicillin-resistant Staphylococcus aureus (EMRSA-15), 6 of whom died, revealed an immunodominant EMRSA-15 antigen at 61 kDa. There was a statistically significant correlate (P < 0.001) between survival and immunoglobulin G to the 61-kDa band. The antigen was identified by sequencing positive clones obtained by screening a genomic expression library of EMRSA-15 with pooled sera from patients taken after the septicemic episode. Eluted antibody reacted with the 61-kDa antigen on immunoblots. The amino terminus was obtained by searching the S. aureus NCTC 8325 and MRSA strain COL databases, and the whole protein was expressed in Escherichia coli TOP 10F'. The derived amino acid sequence showed homology with ABC transporters, with paired Walker A and Walker B motifs and 73% homology to YkpA from Bacillus subtilis. Epitope mapping of the derived amino acid sequence with sera from patients who had recovered from EMRSA-15 septicemia delineated seven epitopes. Three of these epitopes, represented by peptides 1 (KIKVYVGNYDFWYQS), 2 (TVIVVSHDRHFLYNNV), and 3 (TETFLRGFLGRMLFS), were synthesized and used to isolate human recombinant antibodies from a phage antibody display library. Recombinant antibodies against peptides 1 and 2 gave logarithmic reductions in organ colony counts, compared with control groups, in a mouse model of the infection. This study suggests the potential role of an ABC transporter as a target for immunotherapy.

* Corresponding author. Mailing address: NeuTec Pharma plc, 2nd Floor, Clinical Sciences Building, Central Manchester Healthcare Trust, Oxford Road, Manchester M13 9WL, United Kingdom. Phone: 44161 276 4280. Fax: 44161 276 8826. E-mail: dorene{at}labmed.cmht.nwest.nhs.uk.

Infection and Immunity, June 2000, p. 3200-3209, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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