Metabolites Potentiate Nitrofurans in Nongrowing Escherichia coli. Author Sandra Aedo, Juechun Tang, Mark Brynildsen Publication Year 2021 Type Journal Article Abstract 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. Keywords Humans, Escherichia coli Infections, Nitrofurans, Nitrofurantoin, Urinary Tract Infections, Uropathogenic Escherichia coli Journal Antimicrob Agents Chemother Volume 65 Issue 3 Date Published 2021 Feb 17 ISSN Number 1098-6596 DOI 10.1128/AAC.00858-20 Alternate Journal Antimicrob Agents Chemother PMCID PMC8092534 PMID 33361301 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML