Critical Factors Influencing Echinocandin Resistance in Candida glabrata

影响光滑念珠菌棘白菌素耐药性的关键因素

• 批准号: 9111863
• 负责人: David S Perlin
• 金额: $ 52.5万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111863
• 关键词: Alleles; Amino Acid Substitution; Anabolism; Antifungal Agents; Antifungal Therapy; Azole resistance; Azoles; Behavior; Bioinformatics; Calcineurin; Candida; Candida glabrata; Candidiasis; Cell Wall; Cells; Cellular Stress; Characteristics; Chitin; Chitin Synthase; Clinical; Collection; DNA Repair; DNA Repair Pathway; DNA Sequence; Data; Defect; Diagnosis; Disseminated candidiasis; Dose; Drug effect disorder; Drug resistance; Effectiveness; Engineering; Event; Failure; Foundations; Frequencies; Geldanamycin; Genes; Genetic; Genome; Genotype; Health; Heat-Shock Proteins 90; Hot Spot; Human; Immunocompromised Host; In Vitro; Industrial fungicide; Infection; Intervention; Kidney; Knowledge; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Mycoses; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Population; Positioning Attribute; Reporting; Resistance; Response Elements; Role; Serum; Sirolimus; Stress; Therapeutic; Time; Variant; Work; base; biological adaptation to stress; dosage; echinocandin resistance; experience; genomic profiles; glucan synthase; high risk; in vivo; in vivo Model; inhibitor/antagonist; insight; microbial; mortality; mouse model; mutant; nikkomycin; novel; prevent; resistance frequency; resistance mechanism; response; transcriptome; transcriptome sequencing; transcriptomics; whole genome

DESCRIPTION (provided by applicant): Invasive fungal infections due to Candida species are a major cause of morbidity and mortality. Timely diagnosis and appropriate antifungal therapy are critical for patient management. Unfortunately, there are relatively few drug classes available for therapy and they are being compromised by drug resistance. The echinocandins are important antifungal agents for the treatment of patients with Candida infections. However, therapeutic failures are increasingly being reported especially with C. glabrata, which is a leading cause of disseminated candidiasis. Of the major Candida species, echinocandin resistance remains relatively uncommon. Yet, this is not the case for C. glabrata, where resistance now exceeds 13% in certain high-risk centers. It is well- established that clinical echinocandin drug resistance resulting in therapeutic failure is due to amino acid substitutions in highly conserved hot-spot regions of the Fks subunits of glucan synthase. There is a critical need to understand the cellular factors underlying the emergence of Fks-mediated echinocandin resistance. The novel hypothesis being explored in this proposal is that echinocandin resistance in C. glabrata is promoted by cellular factors that stabilize cells in response to drug by creating an unanticipated drug tolerant cell population, which ultimately escapes drug action by the formation of characteristic fks mutations. This hypothesis is supported by pharmacodynamic studies in mice indicating that echinocandin drug therapy at a standard dosage (human equivalent) results in drug tolerant or persistent cell populations. Such behavior is inconsistent with echinocandin drugs as presumed fungicidal agents. Rather, the in vivo data suggests that the echinocandin drugs behave as fungistatic agents at a standard dosage. It is hypothesized that in vivo cells become temporally drug- tolerant by inducing a variety of cellular compensatory mechanisms in response to cell wall stress due to echinocandin action. Cellular and genetic factors promote selection of drug resistant variants with mutations in FKS genes from high burden populations of drug tolerant persistor cells. To better understand echinocandin resistance in C. glabrata, a range of cellular factors will be examined in in vitro and in vivo models for their role in emergence of Fks-mediated echinocandin resistance. Specifically, the importance of compensatory cell wall stress responses, decreased DNA repair, azole resistance, serum, and potential novel genes/pathways will be evaluated using appropriate mutants, along with known inhibitors of these pathways. This work will exploit engineered isogenic mutant strains and a unique collection of serial genetically-matched susceptible and fks-resistant clinical isolates of C. glabrata. These latter isolates will be profiled for changes n the genome and transcriptome for the first time to assess the importance of known mechanisms and elucidate potential new genetic incites underlying resistance emergence. Our detailed molecular studies of echinocandin resistance with clinical isolates over the past decade provide a strong foundation to better understand the molecular basis underlying the emergence of echinocandin resistance in C. glabrata. It is anticipated that this information will provide important new insights and potential intervention strategies to overcome and/or prevent the emergence of echinocandin resistance.

描述（由申请人提供）：由念珠菌引起的侵袭性真菌感染是发病率和死亡率的主要原因。及时诊断和适当的抗真菌治疗对患者管理至关重要。不幸的是，可用于治疗的药物种类相对较少，而且它们正受到耐药性的影响。棘白菌素是治疗念珠菌感染的重要抗真菌药物。然而，越来越多的治疗失败的报道，特别是光滑C.，这是播散性念珠菌病的主要原因。在主要的念珠菌种类中，棘珠菌素耐药性仍然相对罕见。然而，在某些高风险中心，这种情况并非如此，其耐药性现已超过13%。临床棘白菌素耐药导致治疗失败的原因是其中的氨基酸取代