Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, USA.
Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, USA
Antimicrob Agents Chemother. 2021 Feb 17;65(3). doi: 10.1128/AAC.00858-20.
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 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 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 (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.
呋喃妥因（NIT）是一种广谱杀菌抗生素，用于治疗尿路感染。它是一种前体药物，一旦被硝基还原酶激活，就会继续抑制细菌的 DNA、RNA、细胞壁和蛋白质合成。先前的工作表明，NIT 对非生长细菌仍保持相当的活性。在这里，我们发现，在最小或人工尿液培养基中生长到静止期的细菌对 NIT 不敏感。在细胞仍处于非生长状态（其他必需营养素缺失）的条件下补充葡萄糖，使培养物对 NIT 敏感。我们将 NIT 敏感性概念化为多输入“与”门，而缺乏敏感性则表示这些输入中的一个或多个不足。考虑的输入包括激活酶、细胞质中 NIT 的丰度以及 NIT 激活所需的还原当量。我们系统地评估了这些输入中的每一个的贡献，发现 NIT 进口和激活酶的水平都不是缺乏敏感性的因素。相反，有证据表明，还原当量的低丰度是静止期细菌不受 NIT 杀伤的原因，而代谢产物可以使这些细胞重新敏感。我们发现，使用硝基呋喃唑酮时也会出现这种现象，这为硝基呋喃类抗生素建立了一般性。此外，我们观察到，通过代谢物补充，NIT 对静止期尿路致病性大肠杆菌（UPEC）的活性也可以增强。这些发现表明，将硝基呋喃类与特定代谢物结合使用可能会改善简单尿路感染的治疗效果。
