Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment
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 successf...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410781 |
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| author | Tingwang Shi Qiong Wu Zesong Ruan Zhiyuan Luo Wenbo Wang Zhao Guo Yihong Ma Xin Wang Guangyu Chu Han Lin Min Ge Yunfeng Chen |
| author_facet | Tingwang Shi Qiong Wu Zesong Ruan Zhiyuan Luo Wenbo Wang Zhao Guo Yihong Ma Xin Wang Guangyu Chu Han Lin Min Ge Yunfeng Chen |
| author_sort | Tingwang Shi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2342b3c702d3460eb33989780c870a92 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2342b3c702d3460eb33989780c870a922025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202410781Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis TreatmentTingwang Shi0Qiong Wu1Zesong Ruan2Zhiyuan Luo3Wenbo Wang4Zhao Guo5Yihong Ma6Xin Wang7Guangyu Chu8Han Lin9Min Ge10Yunfeng Chen11Department 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 ChinaDepartment of Laboratory Medicine Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine 600 Yishan Road Shanghai 200233 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment 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 ChinaDepartment of Orthopedic Surgery Spine Lab The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 ChinaShanghai 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 ChinaDepartment of Electrical and Electronic Engineering The University of Hong Kong Pokfulam Road Hong Kong 999077 ChinaDepartment 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 ChinaAbstract 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.https://doi.org/10.1002/advs.202410781drug deliverymetabolic reprogrammingosteomyelitissmall colony variantβ‐Lactam resistance |
| spellingShingle | Tingwang Shi Qiong Wu Zesong Ruan Zhiyuan Luo Wenbo Wang Zhao Guo Yihong Ma Xin Wang Guangyu Chu Han Lin Min Ge Yunfeng Chen Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment Advanced Science drug delivery metabolic reprogramming osteomyelitis small colony variant β‐Lactam resistance |
| title | Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment |
| title_full | Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment |
| title_fullStr | Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment |
| title_full_unstemmed | Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment |
| title_short | Resensitizing β‐Lactams by Reprogramming Purine Metabolism in Small Colony Variant for Osteomyelitis Treatment |
| title_sort | resensitizing β lactams by reprogramming purine metabolism in small colony variant for osteomyelitis treatment |
| topic | drug delivery metabolic reprogramming osteomyelitis small colony variant β‐Lactam resistance |
| url | https://doi.org/10.1002/advs.202410781 |
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