Evolutionary selection of trimethoprim-resistant dfrA genes in lytic phages affects phage and host fitness during infection

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-09-26 DOI:10.1126/sciadv.adt4817

Kai Wang, Jikai Xu, Xudong Li, Pengfei Zhu, Ruijie Suo, Xiaowei Lu, Haixin Luo, Li Chen, Rong Wen, Chengbo Zheng, Alejandra Bravo, Mario Soberón, Jinshui Zheng, Ming Sun, Donghai Peng

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Abstract

Temperate phages and prophages are well-known carriers of antibiotic resistance genes (ARGs) facilitating their transmission. In contrast, lytic phages rarely harbor functional ARGs. However, by a lenient threshold search strategy combined with a machine learning approach based on structural similarity, here we identified 9419 potential ARGs within lytic phages. We showed that potential trimethoprim-resistance dihydrofolate reductase (dfrA) genes enriched in lytic phages could confer trimethoprim resistance to Escherichia coli. Sequence analysis revealed that lytic phages rarely transfer these potential dfrA genes into their bacterial hosts. Functional studies showed that these dfrA genes not only enhance phage reproduction in the presence of trimethoprim but also promote bacterial growth during phage infection. These results highlight that abundant functional ARGs were selected in evolution to improve lytic phage reproduction by promoting bacterial growth during infection, suggesting that dfrA genes play important roles in evolutionary mutualism between lytic phages and their hosts.

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抗甲氧苄啶dfrA基因在噬菌体中的进化选择影响了噬菌体和宿主在感染过程中的适应性

温带噬菌体和原噬菌体是众所周知的抗生素耐药基因（ARGs）的载体，促进其传播。相比之下，裂解噬菌体很少含有功能性ARGs。然而，通过宽松的阈值搜索策略结合基于结构相似性的机器学习方法，我们在裂解噬菌体中确定了9419个潜在的ARGs。我们发现在裂解噬菌体中富集的潜在耐甲氧苄啶二氢叶酸还原酶（dfrA）基因可以使甲氧苄啶对大肠杆菌产生耐药性。序列分析显示，裂解噬菌体很少将这些潜在的dfrA基因转移到它们的细菌宿主中。功能研究表明，这些dfrA基因不仅在甲氧苄啶存在下增强噬菌体繁殖，而且在噬菌体感染过程中促进细菌生长。这些结果表明，进化过程中选择了丰富的功能性ARGs，通过促进细菌在感染过程中的生长来改善裂解噬菌体的繁殖，表明dfrA基因在裂解噬菌体与宿主的进化共生中发挥了重要作用。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.