journal article·2025-02Open access

Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment

Tingwang Shi, Qiong Wu, Zesong Ruan, Zhiyuan Luo, Wenbo Wang, Zhao Guo, Yihong Ma, Xin Wang, Guangyu Chu, Han Lin, Min Ge, Yunfeng Chen

Advanced Science· Volume 12· Issue 5

Abstract

Abstract 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.
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Research context

OpenAlex topics: Orthopedic Infections and Treatments · Pneumocystis jirovecii pneumonia detection and treatment · Blood disorders and treatments

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

Department of Orthopedic Surgery Spine Lab The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 China

Joslin‐Beth Israel Deaconess Foot Center and The Rongxiang Xu MD Center for Regenerative Therapeutics Beth Israel Deaconess Medical Center Harvard Medical School Boston MA 02215 USA

Shanghai Institute of Ceramics Chinese Academy of Sciences Research Unit of Nanocatalytic Medicine in Specific Therapy for Serious Disease Chinese Academy of Medical Sciences Shanghai 200050 China

Department of Electrical and Electronic Engineering The University of Hong Kong Pokfulam Road Hong Kong 999077 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Shanghai Shenkang Hospital Development Center · Science and Technology Innovation Plan Of Shanghai Science and Technology Commission

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