Department of Molecular & Biomedical Sciences, University of Mainegrid.21106.34, Orono, Maine, USA.
Graduate School of Biomedical Sciences and Engineering, University of Mainegrid.21106.34, Orono, Maine, USA.
Infect Immun. 2022 Apr 21;90(4):e0062621. doi: 10.1128/iai.00626-21. Epub 2022 Mar 15.
Polymicrobial infections are challenging to treat because we don't fully understand how pathogens interact during infection and how these interactions affect drug efficacy. Candida albicans and Pseudomonas aeruginosa are opportunistic pathogens that can be found in similar sites of infection such as in burn wounds and most importantly in the lungs of CF and mechanically ventilated patients. C. albicans is particularly difficult to treat because of the paucity of antifungal agents, some of which lack fungicidal activity. In this study, we investigated the efficacy of anti-fungal treatment during C. albicans-P. aeruginosa coculture and co-infection in the mucosal zebrafish infection model analogous to the lung. We find that P. aeruginosa enhances the activity of fluconazole (FLC), an anti-fungal drug that is fungistatic , to promote both clearance of C. albicans during co-infection and fungal killing . This synergy between FLC treatment and bacterial antagonism is partly due to iron piracy, as it is reduced upon iron supplementation and knockout of bacterial siderophores. Our work demonstrates that FLC has enhanced activity in clinically relevant contexts and highlights the need to understand antimicrobial effectiveness in the complex environment of the host with its associated microbial communities.
多微生物感染的治疗具有挑战性，因为我们不完全了解病原体在感染过程中如何相互作用，以及这些相互作用如何影响药物疗效。白色念珠菌和铜绿假单胞菌是机会性病原体，可在类似的感染部位发现，如烧伤伤口，尤其是 CF 和机械通气患者的肺部。由于抗真菌药物稀缺，其中一些缺乏杀菌活性，因此白色念珠菌特别难以治疗。在这项研究中，我们研究了在粘膜斑马鱼感染模型中白色念珠菌-铜绿假单胞菌共培养和共感染期间抗真菌治疗的疗效，该模型类似于肺部。我们发现铜绿假单胞菌增强了氟康唑（FLC）的活性，氟康唑是一种具有抑菌作用的抗真菌药物，可促进共感染期间白色念珠菌的清除和真菌杀伤。FLC 治疗与细菌拮抗之间的协同作用部分归因于铁劫持，因为在补充铁和敲除细菌铁载体时，这种协同作用会减少。我们的工作表明，FLC 在临床相关环境中具有增强的活性，并强调需要了解宿主及其相关微生物群落的复杂环境中的抗菌效果。
