South Texas Center for Emerging Infectious Diseases (STCEID), Department of Molecular Microbiology and Immunology, The University of Texas at San Antonio, San Antonio, Texas, USA.
Naval Research Unit-San Antonio (NAMRU-SA), Maxillofacial Injury and Disease Department, San Antonio, Texas, USA.
Antimicrob Agents Chemother. 2023 Feb 16;67(2):e0068622. doi: 10.1128/aac.00686-22. Epub 2023 Jan 23.
Procedures such as solid-organ transplants and cancer treatments can leave many patients in an immunocompromised state. This leads to their increased susceptibility to opportunistic diseases such as fungal infections. Mucormycosis infections are continually emerging and pose a serious threat to immunocompromised patients. Recently there has been a sharp increase in mucormycosis cases as a secondary infection in patients battling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Mucorales fungi are notorious for presenting resistance to most antifungal drugs. The absence of effective means to treat these infections results in mortality rates approaching 100% in cases of disseminated infection. One of the most effective antifungal drug classes currently available is the echinocandins. Echinocandins seem to be efficacious in the treatment of many other fungal infections. Unfortunately, susceptibility testing has found that echinocandins have little to no effect on Mucorales fungi. In this study, we found that the model Mucorales Mucor circinelloides genome carries three copies of the genes encoding the echinocandin target protein β-(1,3)-d-glucan synthase (, , and ). Interestingly, we found that exposing M. circinelloides to micafungin significantly increased the expression of the and genes, resulting in an increased accumulation of β-(1,3)-d-glucan on the cell walls. However, this overexpression of the genes is not directly connected to the intrinsic resistance. Subsequent investigation discovered that the serine/threonine phosphatase calcineurin regulates the expression of and , and the deletion of calcineurin results in a decrease in expression of all three genes. Deletion of calcineurin also results in a lower minimum effective concentration (MEC) of micafungin. In addition, we found that duplication of the gene is also responsible for the intrinsic resistance, in which lack of either or led a lower MEC of micafungin. Together, these findings demonstrate that calcineurin and gene duplication contribute to the intrinsic resistance to micafungin we observe in . .
实体器官移植和癌症治疗等程序会使许多患者处于免疫功能低下状态。这导致他们更容易感染机会性疾病，如真菌感染。毛霉菌病感染不断出现，对免疫功能低下的患者构成严重威胁。最近，在与严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染作斗争的患者中，毛霉菌病作为继发感染的病例急剧增加。毛霉菌科真菌以对大多数抗真菌药物产生耐药性而臭名昭著。由于缺乏有效的治疗方法，这些感染的死亡率在播散性感染病例中接近 100%。目前可用的最有效的抗真菌药物类别之一是棘白菌素类。棘白菌素类似乎对许多其他真菌感染有效。不幸的是，药敏试验发现棘白菌素类对毛霉菌科真菌几乎没有作用。在这项研究中，我们发现模型毛霉菌科毛霉菌circinelloides 基因组携带编码棘白菌素靶蛋白β-(1,3)-d-葡聚糖合酶（，和）的基因的三个副本。有趣的是，我们发现将 M. circinelloides 暴露于米卡芬净会显著增加和基因的表达，导致细胞壁上β-(1,3)-d-葡聚糖的积累增加。然而，这些基因的过表达与固有耐药性没有直接关系。随后的研究发现，丝氨酸/苏氨酸磷酸酶钙调神经磷酸酶调节和基因的表达，钙调神经磷酸酶的缺失导致所有三个基因的表达减少。钙调神经磷酸酶的缺失也导致米卡芬净的最低有效浓度（MEC）降低。此外，我们发现基因的复制也导致固有耐药性，其中缺失或导致米卡芬净的 MEC 降低。总之，这些发现表明钙调神经磷酸酶和基因复制有助于我们在中观察到的米卡芬净的固有耐药性。
