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	Deletion of nudb causes increased susceptibility to antifolates in escherichia coli and salmonella enterica
	Li, Kun1; Li, Ting1; Yang, Shan-shan1; Wang, Xu-De1; Gao, Lei-xin1; Wang, Rui-Qi1; Gu, Jing1; Zhang, Xian-En2; Deng, Jiao-Yu1
刊名	Antimicrobial agents and chemotherapy
	2017-05-01
卷号	61期号:5页码:11
关键词	Nudb Sulfamethoxazole Susceptibility Tetrahydromonapterin Trimethoprim
ISSN号	0066-4804
DOI	10.1128/aac.02378-16
通讯作者	Zhang, xian-en(zhang@wh.iov.cn) ; Deng, jiao-yu(dengjy@wh.iov.cn)
英文摘要	Co-trimoxazole, a fixed-dose combination of sulfamethoxazole (smx) and trimethoprim (tmp), has been used for the treatment of bacterial infections since the 1960s. since it has long been assumed that the synergistic effects between smx and tmp are the consequence of targeting 2 different enzymes of bacterial folate biosynthesis, 2 genes (pabb and nudb) involved in the folate biosynthesis of escherichia coli were deleted, and their effects on the susceptibility to antifolates were tested. the results showed that the deletion of nudb resulted in a lag of growth in minimal medium and increased susceptibility to both smx and tmp. moreover, deletion of nudb also greatly enhanced the bactericidal effect of tmp. to elucidate the mechanism of how the deletion of nudb affects the bacterial growth and susceptibility to antifolates, 7,8-dihydroneopterin and 7,8-dihydropteroate were supplemented into the growth medium. although those metabolites could restore bacterial growth, they had no effect on susceptibilities to the antifolates. reverse mutants of the nudb deletion strain were isolated to further study the mechanism of how the deletion of nudb affects susceptibility to antifolates. targeted sequencing and subsequent genetic studies revealed that the disruption of the tetrahydromonapterin biosynthesis pathway could reverse the phenotype caused by the nudb deletion. meanwhile, overexpression of foim could also lead to increased susceptibility to both smx and tmp. these data suggested that the deletion of nudb resulted in the excess production of tetrahydromonapterin, which then caused the increased susceptibility to antifolates. in addition, we found that the deletion of nudb also resulted in increased susceptibility to both smx and tmp in salmonella enterica. since dihydroneopterin triphosphate hydrolase is an important component of bacterial folate biosynthesis and the tetrahydromonapterin biosynthesis pathway also exists in a variety of bacteria, it will be interesting to design new compounds targeting dihydroneopterin triphosphate hydrolase, which may inhibit bacterial growth and simultaneously potentiate the antimicrobial activities of antifolates targeting other components of folate biosynthesis.
WOS关键词	TRIMETHOPRIM-SULFAMETHOXAZOLE ; PROPHYLAXIS ; INFECTION ; ENZYME ; ENCEPHALITIS ; PURIFICATION ; PNEUMONITIS ; EFFICACY ; THERAPY ; CLONING
WOS研究方向	Microbiology ; Pharmacology & Pharmacy
WOS类目	Microbiology ; Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC MICROBIOLOGY
WOS记录号	WOS:000403532100047
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2373415
专题	武汉病毒研究所
通讯作者	Zhang, Xian-En; Deng, Jiao-Yu
作者单位	1.Chinese Acad Sci, Wuhan Inst Virol, Key Lab Agr & Environm Microbiol, Wuhan, Peoples R China 2.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Li, Kun,Li, Ting,Yang, Shan-shan,et al. Deletion of nudb causes increased susceptibility to antifolates in escherichia coli and salmonella enterica[J]. Antimicrobial agents and chemotherapy,2017,61(5):11.
APA	Li, Kun.,Li, Ting.,Yang, Shan-shan.,Wang, Xu-De.,Gao, Lei-xin.,...&Deng, Jiao-Yu.(2017).Deletion of nudb causes increased susceptibility to antifolates in escherichia coli and salmonella enterica.Antimicrobial agents and chemotherapy,61(5),11.
MLA	Li, Kun,et al."Deletion of nudb causes increased susceptibility to antifolates in escherichia coli and salmonella enterica".Antimicrobial agents and chemotherapy 61.5(2017):11.

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