Global incidence of resistance to current antimicrobial drugs is on the rise, highlighting the urgent need to develop novel antimicrobials. Antimicrobials currently in use typically target pathogen encoded proteins or pathways, leading to selective pressure to acquire resistance. Resistance mechanisms, both acquired and innate, are generally elicited by the cellular stress response. A recent approach targets host factors that the invading microbes rely on for their spread, virulence or survival. It is proposed this approach will produce antimicrobials that are much less likely to select for resistance. This study uses vaccinia virus (VACV) to model the development of resistance to host targeted antimicrobial imatinib, which inhibits the release of enveloped virus.
Previous work has isolated a putative imatinib resistance allele through culturing virus in the presence of imatinib. A mutation in this isolate was identified in the outer envelope viral protein A34. This study aims to characterise the novel A34 resistance mutation as well as another published mutation in A34 (A34K151E), both leading to higher virus release from cells than the parental WR strain. Both alleles show resistance to imatinib treatment, however they do so to differing extents and potentially represent different modes of resistance. The published mutation shows a similar fold reduction in release following imatinib treatment as the parental strain, though total release remains high. This suggests the high release is simply compensating for the reduction following treatment. The novel mutation however has a significantly lower fold reduction following treatment, suggesting a potentially different mode of resistance. Future work will include further characterisation of the novel allele in vitro and in vivo mice studies to determine whether these mutations in A34 restore lethality of VACV in imatinib treated mice.