Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisagrid.5395.a, Pisa, Italy.
Department of Biology, University of Pisagrid.5395.a, Pisa, Italy.
Microbiol Spectr. 2022 Aug 31;10(4):e0124022. doi: 10.1128/spectrum.01240-22. Epub 2022 Jul 25.
species are the main fungal opportunistic pathogens causing systemic infections that are often associated with drug resistance and biofilm production on medical devices. The pressing need for new antifungal agents led to an increased interest in the use of combination therapies. The present study was aimed at investigating potential synergistic activity of the human lactoferrin-derived hLF1-11 peptide with caspofungin against caspofungin-resistant or -susceptible C. albicans, C. parapsilosis, and C. glabrata strains. Synergism was evaluated by the checkerboard assay, measuring cellular metabolic activity against planktonic and sessile cells. A fractional inhibitory concentration (FIC) index of ≤0.5 was interpreted as synergy. Synergism was evaluated by killing assays on planktonic cells. A cell viability assay was performed with biofilm formation inhibition and preformed biofilm. Synergy for killing and viability assays was defined as a ≥2-log-CFU/mL reduction in comparison with the most active constituent. hLF1-11 and caspofungin exerted (i) synergistic effects against planktonic cells of all the tested strains, yielding drastic caspofungin MIC reduction, (ii) synergistic effects on the inhibition of biofilm formation against biofilm producer strains, yielding caspofungin BIC reduction, and (iii) synergistic effects on preformed biofilm assessed by measuring metabolic activity (FIC range, 0.28 to 0.37) against biofilm-producing strains and by cell viability assay in C. albicans SC5314. The synergistic effect observed between caspofungin and hLF1-11 against spp. is of potential clinical relevance, representing a promising novel approach to target caspofungin-resistant species infections. Further studies elucidating the mechanisms of action of such a synergistic effect are needed. The present study describes a synergistic effect between a conventional antifungal drug, caspofungin, and a synthetic peptide derived from human lactoferrin, hLF1-11, against species. These yeasts are able to cause severe systemic fungal infections in immunocompromised hosts. In addition, they can form biofilms in medical implanted devices. Recently, caspofungin-resistant strains have emerged, thus highlighting the need to develop different therapeutic strategies. In studies, this drug combination is able to restore sensitivity to caspofungin in caspofungin-resistant strains of species, both in free-living cells and in cells organized in biofilms. This synergism could represent a promising novel approach to target infections caused by caspofungin-resistant species.
物种是主要的真菌机会性病原体，导致全身感染，这些感染通常与药物耐药性和医疗器械上生物膜的产生有关。新抗真菌药物的迫切需求导致人们对联合治疗的兴趣增加。本研究旨在研究人乳铁蛋白衍生的 hLF1-11 肽与卡泊芬净联合应用对卡泊芬净耐药或敏感的白念珠菌、近平滑念珠菌和光滑念珠菌菌株的潜在协同活性。协同作用通过棋盘试验评估，测量浮游细胞和定殖细胞的细胞代谢活性。分数抑制浓度（FIC）指数≤0.5 被解释为协同作用。通过浮游细胞杀伤试验评估协同作用。采用生物膜形成抑制和已形成生物膜的方法进行细胞活力测定。与最有效成分相比，杀伤和活力测定的协同作用定义为 CFU/mL 减少≥2 对数。hLF1-11 和卡泊芬净对所有测试菌株的浮游细胞均表现出（i）协同作用，导致卡泊芬净 MIC 显著降低，（ii）对生物膜形成的抑制作用具有协同作用，导致卡泊芬净 BIC 降低，以及（iii）通过测量代谢活性（FIC 范围为 0.28 至 0.37）对生物膜产生菌株进行已形成生物膜的评估以及通过细胞活力测定在白念珠菌 SC5314 中评估协同作用。观察到卡泊芬净和 hLF1-11 之间针对 spp. 的协同作用具有潜在的临床相关性，代表了一种针对卡泊芬净耐药的有希望的新方法。需要进一步研究阐明这种协同作用的作用机制。本研究描述了一种常规抗真菌药物卡泊芬净和人乳铁蛋白衍生的合成肽 hLF1-11 之间针对念珠菌属的协同作用。这些酵母能够在免疫功能低下的宿主中引起严重的全身性真菌感染。此外，它们可以在植入医疗设备的生物膜中形成。最近，出现了卡泊芬净耐药的菌株，因此强调需要开发不同的治疗策略。在这些研究中，这种药物组合能够恢复卡泊芬净对念珠菌属的耐药菌株的敏感性，无论是在游离细胞还是在生物膜中形成的细胞中。这种协同作用可能代表一种针对卡泊芬净耐药念珠菌属引起的感染的有希望的新方法。
