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Gallium Porphyrin and Gallium Nitrate Reduce the High Vancomycin Tolerance of MRSA Biofilms by Promoting
Wenyang Xia1, Niya Li2, Haojie Shan1
1Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Abstract:
Biofilms, structured communities of bacterial cells embedded in a self-produced extracellular matrix (ECM) which consists of proteins, polysaccharide intercellular adhesins (PIAs), and extracellular DNA (eDNA), play a key role in clinical infections and are associated with an increased morbidity and mortality by protecting the embedded bacteria against drug and immune response. The high levels of antibiotic tolerance render classical antibiotic therapies impractical for biofilm-related infections. Thus, novel drugs and strategies are required to reduce biofilm tolerance and eliminate biofilm-protected bacteria. Here, we showed that gallium, an iron mimetic metal, can lead to nutritional iron starvation and act as dispersal agent triggering the reconstruction and dispersion of mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms in an eDNA-dependent manner. The extracellular matrix, along with the integral bacteria themselves, establishes the integrated three-dimensional structure of the mature biofilm. The structures and compositions of gallium-treated mature biofilms differed from those of natural or antibiotic-survived mature biofilms but were similar to those of immature biofilms. Similar to immature biofilms, gallium-treated biofilms had lower levels of antibiotic tolerance, and our in vitro tests showed that treatment with gallium agents reduced the antibiotic tolerance of mature MRSA biofilms. Thus, the sequential administration of gallium agents (gallium porphyrin and gallium nitrate) and relatively low concentrations of vancomycin (16 mg/L) effectively eliminated mature MRSA biofilms and eradicated biofilm-enclosed bacteria within 1 week. Our results suggested that gallium agents may represent a potential treatment for refractory biofilm-related infections, such as prosthetic joint infections (PJI) and osteomyelitis, and provide a novel basis for future biofilm treatments based on the disruption of normal biofilm-development processes.
Insights
Gallium disrupts mature biofilms by causing iron starvation, making bacteria more susceptible to antibiotics. Sequential treatment with gallium agents and vancomycin effectively eliminated resistant biofilms and bacteria.
Area of Science:
- Microbiology
- Infectious Diseases
- Materials Science
Background:
- Bacterial biofilms protect microbes from antibiotics and immune responses, complicating treatment of chronic infections.
- Current therapies are often ineffective against mature biofilms due to high antibiotic tolerance.
- Novel strategies are needed to combat biofilm-related infections and reduce associated morbidity and mortality.
Purpose of the Study:
- To investigate gallium's potential as a novel agent to disrupt mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms.
- To determine the mechanism by which gallium affects biofilm structure and antibiotic tolerance.
- To evaluate the efficacy of sequential gallium and vancomycin treatment against MRSA biofilms.
Main Methods:
- Gallium treatment of mature MRSA biofilms.
- Analysis of biofilm structure and composition using microscopy and biochemical assays.
- In vitro testing of antibiotic tolerance and efficacy of sequential treatment regimens.
Main Results:
- Gallium induced nutritional iron starvation, leading to biofilm dispersal and reconstruction dependent on extracellular DNA (eDNA).
- Gallium-altered biofilms resembled immature biofilms, exhibiting reduced antibiotic tolerance.
- Sequential administration of gallium agents and vancomycin eradicated mature MRSA biofilms and enclosed bacteria within one week.
Conclusions:
- Gallium acts as a biofilm dispersal agent and reduces antibiotic tolerance by mimicking iron starvation.
- Gallium agents show promise as a novel therapeutic strategy for refractory biofilm-related infections.
- Targeting biofilm development processes offers a new approach for combating persistent bacterial infections.
