Phenotypic variation during biofilm formation: Implications for anti-biofilm therapeutic design

Various bacterial species cycle between growth phases and biofilm formation, of which the latter facilitates persistence in inhospitable environments. These phases can be generally characterized by one or more cellular phenotype(s), each with distinct virulence factor functionality. In addition, a variety of phenotypes can often be observed within the phases themselves, which can be dependent on host conditions or the presence of nutrient and oxygen gradients within the biofilm itself (i.e., microenvironments). Currently, most anti-biofilm strategies have targeted a single phenotype; this approach has driven effective, yet incomplete, protection due to the lack of consideration of gene expression dynamics throughout the bacteria's pathogenesis. As such, this article provides an overview of the distinct phenotypes found within each biofilm development phase and demonstrates the unique anti-biofilm solutions each phase offers. However, we conclude that a combinatorial approach must be taken to provide complete protection against biofilm forming bacterial and their resulting diseases.