Strategies to potentiate antimicrobial photoinactivation by overcoming resistant phenotypes

Conventional antimicrobial strategies have become increasingly ineffective due to the emergence of multidrug resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered the exploration of alternative treatments and unconventional approaches towards controlling microbial infections. Photodynamic therapy (PDT) was originally established as an anticancer modality and is currently used in the treatment of age-related macular degeneration. The concept of photodynamic inactivation requires cell exposure to light energy, typically wavelengths in the visible region that causes the excitation of photosensitizer molecules either exogenous or endogenous, which results in the production of reactive oxygen species (ROS). ROS produce cell inactivation and death through modification of intracellular components. The versatile characteristics of PDT prompted its investigation as an anti-infective discovery platform. Advances in understanding of microbial physiology have shed light on a series of pathways, and phenotypes that serve as putative targets for antimicrobial drug discovery. Investigations of these phenotypic elements in concert with PDT have been reported focused on multidrug efflux systems, biofilms, virulence and pathogenesis determinants. In many instances the results are promising but only preliminary and require further investigation. This review discusses the different antimicrobial PDT strategies and highlights the need for highly informative and comprehensive discovery approaches. In just 20 years antimicrobial photodynamic therapy (PDT) has emerged as a discovery and development platform inspiring a proliferation of light-based antimicrobial explorations worldwide. However, the potential for microbial resistance development using PDT remains under-investigated. Studies of resistance have been sporadic but they are rapidly increasing, with recent reports examining key elements of the microbial phenotype. These include multidrug efflux systems, biofilm, spore formation, virulence and pathogenicity determinants. The emerging consensus is that the effectiveness of PDT may be profoundly impacted by all these systems, but the exact mechanisms of these effects remain elusive. For example, an array of studies suggests that antimicrobial photosensitizers are substrates of multidrug efflux systems. An evolving antimicrobial discovery concept is based on the exploration of synergies between photosensitizers and small molecules efflux pump inhibitors. PS photosensitizer (red), EPI efflux pump inhibitor (green).