DNA viruses and retroviruses consume large quantities of deoxynucleotides (dNTPs) when replicating. The human antiviral factor SAMHD1 takes advantage of this vulnerability in the viral lifecycle, and inhibits viral replication by degrading dNTPs into their constituent deoxynucleosides and inorganic phosphate. Here, we report that bacteria use a similar strategy to defend against bacteriophage infection. We identify a family of defensive bacterial deoxycytidine triphosphate (dCTP) deaminase proteins that convert dCTP into deoxyuracil nucleotides in response to phage infection. We also identify a family of phage resistance genes that encode deoxyguanosine triphosphatase (dGTPase) enzymes, which degrade dGTP into phosphate-free deoxyguanosine and are distant homologues of human SAMHD1. Our results suggest that bacterial defensive proteins deplete specific deoxynucleotides (either dCTP or dGTP) from the nucleotide pool during phage infection, thus starving the phage of an essential DNA building block and halting its replication. Our study shows that manipulation of the dNTP pool is a potent antiviral strategy shared by both prokaryotes and eukaryotes.

DNA 病毒和逆转录病毒在复制时会消耗大量的脱氧核苷酸 (dNTP)。人类抗病毒因子 SAMHD1 利用病毒生命周期中的这种脆弱性，通过将 dNTP 降解为其组成的脱氧核苷和无机磷酸盐来抑制病毒复制。在这里，我们报告细菌使用类似的策略来防御噬菌体感染。我们确定了一个防御性细菌脱氧胞苷三磷酸 (dCTP) 脱氨酶蛋白家族，可将 dCTP 转化为脱氧尿嘧啶核苷酸以响应噬菌体感染。我们还鉴定了一个编码脱氧鸟苷三磷酸酶 (dGTPase) 酶的噬菌体抗性基因家族，这些酶将 dGTP 降解为无磷酸盐的脱氧鸟苷，并且是人类 SAMHD1 的遥远同源物。我们的研究结果表明，细菌防御蛋白会在噬菌体感染期间从核苷酸库中消耗特定的脱氧核苷酸（dCTP 或 dGTP），从而使噬菌体缺乏必要的 DNA 构建块并停止其复制。我们的研究表明，操纵 dNTP 池是原核生物和真核生物共有的有效抗病毒策略。