Viral resistance evolution fully escapes a rationally designed lethal inhibitor.
Viral resistance evolution fully escapes a rationally designed lethal inhibitor.
复制标题
病毒耐药性的进化完全逃脱了合理设计的致命抑制剂的影响。
DOI：
10.1093/molbev/msp111
复制
发表时间：
2009
影响因子：
10.7
通讯作者：
Bull,JamesJ
中科院分区：
文献类型：
--
作者：
Keller,ThomasE;Molineux,IanJ;Bull,JamesJ
Please try later.
Viruses are notoriously capable of evolving resistance to drugs. However, if the endpoint of resistance evolution is only partial escape, a feasible strategy should be to stack drugs, so the combined effect of partial inhibition by several drugs results in net inhibition. Assessing the feasibility of this approach requires quantitative data on viral fitness before and after evolution of resistance to a drug, as done here with bacteriophage T7. An inhibitory gene expressed from a phage promoter aborts wild-type T7 infections. The effect is so severe that the phage population declines when exposed to the inhibitor but expands a billion-fold per hour in its absence. In prior work, T7 evolved modest resistance to this inhibitor, an expected result. Given the nature of the inhibitor, that it used the phage's own promoter to target the phage's destruction, we anticipated that resistance evolution would be limited as the phage may need to evolve a new regulatory system, with simultaneous changes in its RNA polymerase (RNAP) and many of its promoters to fully escape inhibition. We show here that further adaptation of the partially resistant phage led to complete resistance. Resistance evolution was due to three mutations in the RNAP gene and two other genes; unexpectedly, no changes were observed in promoters. Consideration of other mechanisms of T7 inhibition leaves hope that permanent inhibition of viral growth with drugs can in principle be achieved.