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.