Ravishankar Srikanth, Conte Antonietta Lucia, Carrasco Aliaga Stacy Julisa, Baldelli Valerio, Nielsen Karen Leth, Paroni Moira, Conte Maria Pia, Landini Paolo, Rossi Elio
Department of Biosciences, University of Milan, Milan, Lombardy, Italy.
Department of Public Health and Infectious Diseases, Sapienza University, Rome, Lazio, Italy.
Antimicrob Agents Chemother. 2025 Apr 3;69(5):e0028025. doi: 10.1128/aac.00280-25.
Biofilm can enhance antibiotic tolerance in bacteria, making treatment of biofilm-associated infections in clinical settings a significant challenge. 5-Fluorocytosine (5-FC), an FDA-approved drug mostly used as an antifungal, can hinder biofilm formation and production of virulence factors in Gram-negative bacteria. In this study, we tested 5-FC on nine uropathogenic (UPEC) strains plus a fecal isolate. Our data indicated that 5-FC reduced curli fiber gene expression and inhibited virulence factors in UPEC strains. Unlike what was observed in other microorganisms, 5-FC antivirulence and antibiofilm properties were unaffected by either growth temperature or the medium pH, which might prove critical in urinary tract infection (UTI) treatment. Additionally, 5-FC impaired the expression of various UPEC virulence factors, including secreted toxins and type I and P fimbriae, thus leading to decreased UPEC adherence to bladder epithelial cells and improved survival of host cells. Finally, we found that a combination of 5-FC with β-lactams, but not other classes of antibiotics, significantly lowered the viability of bacteria in preformed biofilms. Despite a small set of pathogenic strains and an infection model, our findings strongly suggest that 5-FC might be a possible candidate as an antivirulence agent, particularly in a synergistic approach with β-lactam antibiotics.
生物膜可增强细菌对抗生素的耐受性，这使得在临床环境中治疗与生物膜相关的感染成为一项重大挑战。5-氟胞嘧啶（5-FC）是一种经美国食品药品监督管理局（FDA）批准的药物，主要用作抗真菌药，它可以阻碍革兰氏阴性菌生物膜的形成和毒力因子的产生。在本研究中，我们对9株尿路致病性大肠杆菌（UPEC）菌株以及1株粪便分离株进行了5-FC测试。我们的数据表明，5-FC可降低卷曲纤维基因的表达并抑制UPEC菌株中的毒力因子。与在其他微生物中观察到的情况不同，5-FC的抗毒力和抗生物膜特性不受生长温度或培养基pH值的影响，这在尿路感染（UTI）治疗中可能至关重要。此外，5-FC会损害各种UPEC毒力因子的表达，包括分泌毒素以及I型和P型菌毛，从而导致UPEC对膀胱上皮细胞的粘附减少，并提高宿主细胞的存活率。最后，我们发现5-FC与β-内酰胺类抗生素联合使用（而非与其他类抗生素联合使用）可显著降低预先形成的生物膜中细菌的活力。尽管我们使用的致病菌株数量较少且感染模型单一，但我们的研究结果强烈表明，5-FC可能是一种潜在的抗毒力药物，特别是与β-内酰胺类抗生素联合使用时。
