A Hybrid Drug Limits Resistance by Evading the Action of the Multiple Antibiotic Resistance Pathway

被引:23
作者
Wang, Kathy K. [1 ]
Stone, Laura K. [1 ]
Lieberman, Tami D. [1 ]
Shavit, Michal [2 ]
Baasov, Timor [2 ]
Kishony, Roy [1 ,3 ]
机构
[1] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA USA
[2] Technion Israel Inst Technol, Schulich Fac Chem, Haifa, Israel
[3] Technion Israel Inst Technol, Fac Biol & Comp Sci, Haifa, Israel
基金
欧洲研究理事会; 以色列科学基金会; 美国国家卫生研究院; 美国国家科学基金会;
关键词
antibiotic resistance; experimental evolution; hybrid drug; multidrug resistance; MULTIDRUG EFFLUX TRANSPORTER; IN-VITRO EVALUATION; ESCHERICHIA-COLI; COLLATERAL SENSITIVITY; MAR MUTANTS; EVOLUTION; DESIGN; MODE; CEPHALOSPORIN; RO-23-9424;
D O I
10.1093/molbev/msv243
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:492 / 500
页数:9
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