Shi Tingwang, Wu Qiong, Ruan Zesong, Luo Zhiyuan, Wang Wenbo, Guo Zhao, Ma Yihong, Wang Xin, Chu Guangyu, Lin Han, Ge Min, Chen Yunfeng
Department of Orthopedic Surgery, Shanghai Institute of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.
Department of Laboratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.
Adv Sci (Weinh). 2025 Feb;12(5):e2410781. doi: 10.1002/advs.202410781. Epub 2024 Dec 10.
Small colony variant (SCV) is strongly linked to antibiotic resistance and the persistence of osteomyelitis. However, the intrinsic phenotypic instability of SCV has hindered a thorough investigation of its pathogenic mechanisms. In this study, phenotypically stable SCV strains are successfully recovered from clinical specimens, characterized by elevated drug resistance and reduced immunogenicity. Multi-omics analysis revealed that the acquired high drug resistance is associated with altered flux in the purine metabolism pathway, attributable to mutations in the hypoxanthine phosphoribosyltransferase (hpt) gene. Furthermore, this study innovatively discovered that lonidamine, an inhibitor of cellular energy metabolism, can effectively mitigate SCV resistance to β-lactam antibiotics, thereby facilitating its eradication. The underlying mechanism involves the reprogramming of purine metabolism. Therefore, a co-delivery system for lonidamine and oxacillin is constructed with amino-modified dendritic mesoporous silica as a carrier, which showed high efficacy and safety in combating SCV both in vitro and in vivo experiments. Overall, this study elucidated the pathogenic mechanisms of a class of clinically isolated SCV isolates with hpt mutations and provided a paradigm for treating SCV-associated osteomyelitis by reprogramming purine metabolism.
小菌落变异株（SCV）与抗生素耐药性及骨髓炎的持续存在密切相关。然而，SCV固有的表型不稳定性阻碍了对其致病机制的深入研究。在本研究中，成功从临床标本中分离出表型稳定的SCV菌株，其特征为耐药性增强和免疫原性降低。多组学分析表明，获得性高耐药性与嘌呤代谢途径通量改变有关，这归因于次黄嘌呤磷酸核糖转移酶（hpt）基因突变。此外，本研究创新性地发现，细胞能量代谢抑制剂氯尼达明可有效减轻SCV对β-内酰胺类抗生素的耐药性，从而促进其根除。潜在机制涉及嘌呤代谢的重编程。因此，以氨基修饰的树枝状介孔二氧化硅为载体构建了氯尼达明和苯唑西林的共递送系统，该系统在体外和体内实验中对抗SCV均显示出高效性和安全性。总体而言，本研究阐明了一类具有hpt突变的临床分离SCV菌株的致病机制，并为通过重编程嘌呤代谢治疗SCV相关骨髓炎提供了范例。
