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  3. A strategy to re-sensitise drug-resistant Gram-positive bacteria to oxazolidinone-class antibiotics

A strategy to re-sensitise drug-resistant Gram-positive bacteria to oxazolidinone-class antibiotics

  • EBioMedicine. 2025 Sep:119:105914. doi: 10.1016/j.ebiom.2025.105914.
Qi Zhang 1,  Yang Yang 1,  Ying Yang 1,  Jin Shang 1,  Shan Su 2,  Peng Gao 3,  Xiao-Xiao Li 2,  Zhao Liu 4,  Richard Yi-Tsun Kao 5,  Ben Chi-Bun Ko 6,  Benjamin Thompson 7,  Qian Zhao 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong; Centre for Eye and Vision Research, Hong Kong.
  • 2 State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen, China.
  • 3 Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Sassoon Road, Hong Kong.
  • 4 Centre for Eye and Vision Research, Hong Kong.
  • 5 Department of Microbiology, The University of Hong Kong, Sassoon Road, Hong Kong.
  • 6 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
  • 7 Centre for Eye and Vision Research, Hong Kong; School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, Canada.
  • 8 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong. Electronic address: q.zhao@polyu.edu.hk.
PMID: 40912150 DOI: 10.1016/j.ebiom.2025.105914
Abstract

Background: Multidrug-resistant Bacterial infections have high mortality rates and few treatment options. Synergistic combinations may improve clinical outcome but traditional strategies often damage healthy microbiome. Oxazolidinone-class Antibiotics are typical last-resort drugs for treating drug-resistant Bacterial infections but are becoming less effective due to resistance development.

Methods: After high-throughput screening, synergy was further assessed by in vitro indices (like fractional inhibitory concentration index, biofilm formation and resistance development) and in vivo symptoms in Animals with skin and ocular Bacterial infections (and ocular microbiome extraction analysis). Proteomics, chemical synthesis, multi-microscopy techniques and Antibiotic real-time/kinetic accumulation were employed to explore mechanisms and expand translational applications.

Findings: Combining phosphorylated oxazolidinone-class Antibiotics with positively charged compounds (lysozyme as native representative) resulted in broad-spectrum drug re-sensitisation. In representative combination, urea cycle was disrupted to alkalinise cytoplasm, which subsequently activated Alkaline Phosphatase to promote conversion of phosphorylated prodrug to active form. By introducing concept of restored healthy microbiome as the evaluated index in Antibiotic therapy, we confirmed excellent translational and microbiome-friendly potential of this strategy in clinical settings because it not only inhibited biofilm formation and development of drug-resistant mutations in vitro, but also alleviated symptoms in infected Animals including the restoration of healthy microbiome.

Interpretation: As both agents have excellent safety profiles, such clinical investigation may immediately be contemplated in humans. Translationally, scientists benefit from strategy by simultaneously achieving greater efficacy (>500-fold re-sensitisation) and higher safety (prodrug-based and microbiome-friendly strategy especially when active form may be toxic).

Funding: Collaborative Research Funds from Research Grants Council (C5033-19E).

Keywords

Antimicrobial resistance; Lysozyme; Ocular microbiome; Oxazolidinone-class antibiotics; Phosphorylated prodrugs; Tedizolid phosphate.

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