Research highlights Bile protects various pathogenic fungi from antifungals Bile lipids increase antifungal trapping efficiency of conjugated bile salts Polyunsaturated fatty acids mediate azole resistance of conjugated bile salts Pathogen elimination from biliary system depends on antifungals not trapped in bile 2017). The resulting reduction in the bioavailability of drugs in the biliary system and 60 possibly also in the intestine might thereby not only prevent the clearance of pathogens from 61 these host niches, but might also lead to the development of drug resistant strains.
62Accordingly, a recent study revealed the emergence of echinocandin resistant Candida 63 species in liver transplant recipients after treatment with caspofungin (Prigent et al., 2017).
64Resistant strains were mainly isolated from the digestive system implying that a reduced 65 bioavailability of drugs might have caused this emergence (Prigent et al., 2017 was well tolerated by all strains, except for the C. neoformans isolates that revealed a slight, 185 but significant reduction in growth rate (Fig.1). Subsequently, we determined amphotericin B
186concentrations that suppress growth of the respective species. S. cerevisiae and C. glabrata 187 showed no growth at 0.5 µg/ml, the two Aspergillus species did not proliferate at 1 µg/ml and 188 the two C. neoformans strains did not grow in the presence of 2 µg/ml of amphotericin B
189( Fig.1). against caspofungin and amphotericin B (Fig. 3A). Here, we used a sub-protective 221 concentration of 10 mg/ml of taurocholate at which C. albicans was sensitive against 2 µg/ml 222 caspofungin and 4 µg/ml amphotericin B. Similarly, the phospholipid lecithin alone, in a 223 concentration of up to 10 mM, was not protective. However, 2.5 mM of lecithin enhanced the 224 protective effect of taurocholate and mediated caspofungin and amphotericin B resistance
225( Fig. 3A). Subsequently, the addition of phospholipids on fluconazole protection was 226 analysed, whereby the protective effect with either taurocholate, taurodeoxycholate or bile 227 was tested (Fig. 3B) defect was observed by the addition of myristic (C14) and palmitic (C16) acid (Fig 5A).
249However, despite the presence of 10 mg/ml taurocholate, palmitic acid was not well 250 solubilised and produced solid particles in the growth media at 37°C. Therefore, we
255Furthermore, similar to lecithin, a determination of the CMC value of taurocholate revealed 256 that myristic acid did not significantly reduce the concentration of taurocholate required to 257 form micelles (Fig. 4). Therefore, similar to phospholipids, saturated fatty acids reduce the Fig. 6A and 6B). A single species of 281 these polyunsaturated fatty acids was also able to confer resistance in a concentration 282 dependent manner when combined with taurocholate. In these analyses, arachidonic acid 283 showed a higher protective effect compared to linolenic acid. (Fig. 6C) (Fig. 6D). Unexpectedly, while neither phospholipids nor saturated fatty acids 292 significantly ...