Affiliation:
1. Department of Anesthesiology and Surgical Intensive Care Unit Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200092 China
2. Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases Shanghai Institute of Traumatology and Orthopaedics Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
3. Department of Pharmacy Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200092 China
4. Wellman Center for Photomedicine Massachusetts General Hospital Department of Dermatology Harvard Medical School 50 Blossom Street Boston MA 02114 USA
Abstract
AbstractMetallo‐β‐lactamases (MBLs) represent a prevalent resistance mechanism in Gram‐negative bacteria, rendering last‐line carbapenem‐related antibiotics ineffective. Here, a bioresponsive sliver peroxide (Ag2O2)‐based nanovesicle, named Ag2O2@BP‐MT@MM, is developed as a broad‐spectrum MBL inhibitor for combating MBL‐producing bacterial pneumonia. Ag2O2 nanoparticle is first orderly modified with bovine serum albumin and polydopamine to co‐load meropenem (MER) and [5‐(p‐fluorophenyl)‐2‐ureido]‐thiophene‐3‐carboxamide (TPCA‐1) and then encapsulated with macrophage membrane (MM) aimed to target inflammatory lung tissue specifically. The resultant Ag2O2@BP‐MT@MM effectively abrogates MBL activity by displacing the Zn2+ cofactor in MBLs with Ag+ and displays potent bactericidal and anti‐inflammatory properties, specific targeting abilities, and great bioresponsive characteristics. After intravenous injection, the nanoparticles accumulate prominently at infection sites through MM‐mediated targeting . Ag+ released from Ag2O2 decomposition at the infection sites effectively inhibits MBL activity and overcomes the resistance of MBL‐producing bacteria to MER, resulting in synergistic elimination of bacteria in conjunction with MER. In two murine infection models of NDM‐1+ Klebsiella pneumoniae‐induced severe pneumonia and NDM‐1+ Escherichia coli‐induced sepsis‐related bacterial pneumonia, the nanoparticles significantly reduce bacterial loading, pro‐inflammatory cytokine levels locally and systemically, and the recruitment and activation of neutrophils and macrophages. This innovative approach presents a promising new strategy for combating infections caused by MBL‐producing carbapenem‐resistant bacteria.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Shanghai Municipality
Shanghai Municipal Health Commission
Subject
Mechanical Engineering,Mechanics of Materials,General Materials Science