Metabolites Potentiate Nitrofurans in Nongrowing Escherichia coli

硝基呋喃 呋喃妥因 前药 大肠杆菌 微生物学 抗生素 细菌 泌尿系统 核糖核酸 化学 肠杆菌科 生物 生物化学 抗生素耐药性 基因 遗传学 内分泌学
作者
Sandra Aedo,Juechun Tang,Mark P. Brynildsen
出处
期刊:Antimicrobial Agents and Chemotherapy [American Society for Microbiology]
卷期号:65 (3) 被引量:11
标识
DOI:10.1128/aac.00858-20
摘要

Nitrofurantoin (NIT) is a broad-spectrum bactericidal antibiotic used in the treatment of urinary tract infections. It is a prodrug that once activated by nitroreductases goes on to inhibit bacterial DNA, RNA, cell wall, and protein synthesis. Previous work has suggested that NIT retains considerable activity against nongrowing bacteria. Here, we have found that Escherichia coli grown to stationary phase in minimal or artificial urine medium is not susceptible to NIT. Supplementation with glucose under conditions where cells remained nongrowing (other essential nutrients were absent) sensitized cultures to NIT. We conceptualized NIT sensitivity as a multi-input AND gate and lack of susceptibility as an insufficiency in one or more of those inputs. The inputs considered were an activating enzyme, cytoplasmic abundance of NIT, and reducing equivalents required for NIT activation. We systematically assessed the contribution of each of these inputs and found that NIT import and the level of activating enzyme were not contributing factors to the lack of susceptibility. Rather, evidence suggested that the low abundance of reducing equivalents is why stationary-phase E. coli are not killed by NIT and catabolites can resensitize those cells. We found that this phenomenon also occurred when using nitrofurazone, which established generality to the nitrofuran antibiotic class. In addition, we observed that NIT activity against stationary-phase uropathogenic E. coli (UPEC) could also be potentiated through metabolite supplementation. These findings suggest that the combination of nitrofurans with specific metabolites could improve the outcome of uncomplicated urinary tract infections.
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