Chakraborty Shuvechha, Palanikumar Indumathi, Gune Yash, Venkatesh K V, Raman Karthik, Idicula-Thomas Susan
Biomedical Informatics Centre, ICMR-National Institute for Research in Reproductive and Child Health, Mumbai, Maharashtra, 400012, India.
Department of Biotechnology, Bhupat Jyoti Mehta School of Biosciences, Indian Institute of Technology (IIT) Madras, Chennai, 600036, India.
Cell Commun Signal. 2025 Aug 4;23(1):362. doi: 10.1186/s12964-025-02306-9.
Candida albicans, responsible for approximately 70% of all Candida infections, is a leading cause of invasive candidiasis and poses a significant global health threat. With the emergence of drug-resistant strains, mortality rates have reached a staggering 63.6% in severe cases, complicating treatment options and demanding the discovery of novel therapeutic targets. To address this pressing need, using a unique multidisciplinary approach, we attempted to identify some the critical metabolic pathways that can be targeted to modulate the virulence of CAL. Condition-specific genome-scale metabolic models (GSMMs), along with a novel integrated host-CAL model developed in this study, highlighted the central role of arginine (Arg) metabolism and uncovered ALT1, an arginine biosynthesis enzyme, as a critical metabolic vulnerability in CAL virulence. Heightened expression of arginine biosynthesis genes indicated that increased arginine synthesis mainly occurred through proline intermediates during host interaction. Significantly impaired virulence and in vivo pathogenicity of ALT1-deleted CAL highlighted the potential of targeting arginine metabolism as a novel strategy to combat antifungal resistance and underscored the power of integrating systems biology with experimental approaches in identifying new therapeutic targets.
白色念珠菌约占所有念珠菌感染的70%，是侵袭性念珠菌病的主要病因，对全球健康构成重大威胁。随着耐药菌株的出现，严重病例的死亡率已达到惊人的63.6%，使治疗选择变得复杂，迫切需要发现新的治疗靶点。为满足这一紧迫需求，我们采用独特的多学科方法，试图确定一些可靶向调节白色念珠菌毒力的关键代谢途径。特定条件下的基因组规模代谢模型（GSMMs）以及本研究中开发的新型宿主-白色念珠菌整合模型，突出了精氨酸（Arg）代谢的核心作用，并发现精氨酸生物合成酶ALT1是白色念珠菌毒力的关键代谢弱点。精氨酸生物合成基因的表达增强表明，在宿主相互作用期间，精氨酸合成增加主要通过脯氨酸中间体进行。缺失ALT1的白色念珠菌毒力和体内致病性显著受损，突出了靶向精氨酸代谢作为对抗抗真菌耐药性的新策略的潜力，并强调了将系统生物学与实验方法相结合在识别新治疗靶点方面的作用。
