Wang Kathy K, Stone Laura K, Lieberman Tami D, Shavit Michal, Baasov Timor, Kishony Roy
Department of Systems Biology, Harvard Medical School, Boston, MA.
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa, Israel.
Mol Biol Evol. 2016 Feb;33(2):492-500. doi: 10.1093/molbev/msv243. Epub 2015 Nov 3.
Hybrid drugs are a promising strategy to address the growing problem of drug resistance, but the mechanism by which they modulate the evolution of resistance is poorly understood. Integrating high-throughput resistance measurements and genomic sequencing, we compared Escherichia coli populations evolved in a hybrid antibiotic that links ciprofloxacin and neomycin B with populations evolved in combinations of the component drugs. We find that populations evolved in the hybrid gain less resistance than those evolved in an equimolar mixture of the hybrid's components, in part because the hybrid evades resistance mediated by the multiple antibiotic resistance (mar) operon. Furthermore, we find that the ciprofloxacin moiety of the hybrid inhibits bacterial growth whereas the neomycin B moiety diminishes the effectiveness of mar activation. More generally, comparing the phenotypic and genotypic paths to resistance across different drug treatments can pinpoint unique properties of new compounds that limit the emergence of resistance.
杂合药物是应对日益严重的耐药性问题的一种有前景的策略，但它们调节耐药性演变的机制却鲜为人知。我们整合了高通量耐药性测量和基因组测序技术，将在连接环丙沙星和新霉素B的杂合抗生素中进化的大肠杆菌群体与在组成该杂合药物的各成分药物组合中进化的群体进行了比较。我们发现，在杂合药物中进化的群体获得的耐药性比在该杂合药物各成分等摩尔混合物中进化的群体要少，部分原因是该杂合药物能规避由多重耐药性（mar）操纵子介导的耐药性。此外，我们发现该杂合药物的环丙沙星部分抑制细菌生长，而新霉素B部分则降低mar激活的有效性。更普遍地说，比较不同药物处理下耐药性的表型和基因型路径可以确定限制耐药性出现的新化合物的独特特性。
