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JAC Advance Access originally published online on February 25, 2008
Journal of Antimicrobial Chemotherapy 2008 61(5):1044-1047; doi:10.1093/jac/dkn057
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

A single drug-resistance mutation in HSV-1 UL52 primase points to a difference between two helicase–primase inhibitors in their mode of interaction with the antiviral target

Subhajit Biswas1, Gerald Kleymann2, Mihaiela Swift1, Laurence S. Tiley1, Jonathan Lyall1, Jesús Aguirre-Hernández1 and Hugh J. Field1,*

1 Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK 2 Leopoldshöherstraβe 7, D-32107 Bad-Salzuflen, Germany

Received 28 November 2007; returned 17 January 2008; revised 23 January 2008; accepted 24 January 2008

* Corresponding author. Tel: +44-1223-330810; Fax: +44-1223-337610; E-mail: hjf10{at}cam.ac.uk

Objectives: To investigate the mechanism of action of the helicase–primase inhibitors (HPIs) BAY 57-1293 and BILS 22 BS by selection and characterization of drug-resistant herpes simplex virus (HSV)-1 mutants.

Methods: HSV-1 mutants were selected using BAY 57-1293 in Vero cells. Resistance mutations identified in the UL5 helicase or UL52 primase genes were validated by marker transfer. Cross-resistance to the structurally distinct BILS 22 BS was measured by ID50 determinations.

Results: (i) A single mutation (UL52: A899T) confers 43-fold resistance to BAY 57-1293, but does not confer any resistance to BILS 22 BS. (ii) A double mutant (UL52: A899T and UL5: K356T) is 2500-fold resistant to BAY 57-1293, which is more than 17 times the sum of fold-resistance due to the individual mutations, UL52: A899T (43-fold) and UL5: K356T (100-fold). (iii) Virus containing the single helicase mutation and the double mutant with mutations in both helicase and primase showed equal resistance to BILS 22 BS (70-fold).

Conclusions: By measuring the relative inhibitory concentrations required to overcome particular mutations in the helicase and primase proteins, evidence was obtained that BAY 57-1293 interacts with both components of the helicase–primase complex to achieve maximum potency, whereas for BILS 22BS, this may not be the case. Furthermore, our observations suggest that BAY 57-1293 interacts simultaneously with UL5 and UL52. Overall, the results suggest that these two potent HPIs interact differently with the helicase–primase complex.

Keywords: herpes simplex virus , BAY 57-1293 , BILS 22 BS , mutation


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