Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.
Antimicrob Agents Chemother. 2019 Jan 29;63(2). doi: 10.1128/AAC.01577-18. Print 2019 Feb.
We show that trimethoprim (TMP), an antibiotic in current use, displays a strong synergistic effect on mutagenesis in when paired with the base analog 2-aminopurine (2AP), resulting in a 35-fold increase in mutation frequencies in the -Rif system. Combination therapies are often employed both as antibiotic treatments and in cancer chemotherapy. However, mutagenic effects of these combinations are rarely examined. An analysis of the mutational spectra of TMP, 2AP, and their combination indicates that together they trigger a response via an alteration in deoxynucleoside triphosphate (dNTP) ratios that neither compound alone can trigger. A similar, although less strong, response is seen with the frameshift mutagen ICR191 and 2AP. These results underscore the need for testing the effects on mutagenesis of combinations of antibiotics and chemotherapeutics.
我们表明，当与碱基类似物 2-氨基嘌呤（2AP）配对时，当前使用的抗生素甲氧苄啶（TMP）在时表现出强烈的协同诱变作用，导致 - Rif 系统中的突变频率增加 35 倍。联合疗法通常既用于抗生素治疗，也用于癌症化疗。然而，这些组合的诱变效应很少被检查。对 TMP、2AP 及其组合的突变谱分析表明，它们一起通过脱氧核苷三磷酸（dNTP）比值的改变引发反应，而单独使用任何一种化合物都无法引发这种反应。类似的，但强度较小的反应也发生在移码诱变剂 ICR191 和 2AP 中。这些结果强调了需要测试抗生素和化疗药物组合对诱变的影响。
