Carlson Tyler, Lupinacci Emily, Moseley Katie, Chandrasekaran Srikripa
Department of Biology, Furman University, 3300 Poinsett Highway, Townes 171-G, Greenville SC 29613, USA.
FEMS Microbiol Lett. 2021 May 3;368(7). doi: 10.1093/femsle/fnab040.
Cryptococcus neoformans is a leading cause of fungal meningitis in immunocompromized populations. Amphotericin B (AMB) and fluconazole (FLC) are common anticryptococcal agents. AMB treatment leads to severe side-effects. In contrast, FLC-based therapy is relatively safe, although C. neoformans often develops resistance to this drug. C. neoformans must adapt to the challenging environment of the human host. Environmental effects on potency of AMB and FLC and development of drug resistance remain poorly characterized. Here, the effects of nutrients, temperature and antioxidants on susceptibility of C. neoformans towards FLC and AMB were investigated. Limited nutrients led to a decrease and an increase of sensitivity towards FLC and AMB, respectively. Co-treatment with various antioxidants also demonstrated reciprocal effects on susceptibility towards FLC and AMB. In contrast, elevated temperature increased the efficacy of both drugs, although the effect on FLC was more drastic as compared to that of AMB. In addition, temperatures of 37°C and above prevented development of FLC resistance. Our study pointed to a critical role of the environment on susceptibility towards AMB and FLC and revealed reciprocal effects towards these antifungal drugs, reflecting contrasting modes of action of AMB and FLC.
新型隐球菌是免疫功能低下人群真菌性脑膜炎的主要病因。两性霉素B（AMB）和氟康唑（FLC）是常用的抗隐球菌药物。AMB治疗会导致严重的副作用。相比之下，基于FLC的疗法相对安全，尽管新型隐球菌经常对这种药物产生耐药性。新型隐球菌必须适应人类宿主具有挑战性的环境。环境对AMB和FLC效力以及耐药性发展的影响仍未得到充分表征。在此，研究了营养物质、温度和抗氧化剂对新型隐球菌对FLC和AMB敏感性的影响。营养物质有限分别导致对FLC的敏感性降低和对AMB的敏感性增加。与各种抗氧化剂联合处理也显示出对FLC和AMB敏感性的相互影响。相比之下，温度升高会提高两种药物的疗效，尽管与AMB相比，对FLC的影响更为显著。此外，37°C及以上温度可防止FLC耐药性的产生。我们的研究指出环境对AMB和FLC敏感性的关键作用，并揭示了对这些抗真菌药物的相互影响，反映了AMB和FLC不同的作用模式。
