Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches.

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.

The potential energy surfaces for the fragmentation of the radical anions of p-nitrochlorobenzene and p- and m-chloroacetophenones were explored using first principle methods. The behavior of these compounds, stabilized by pi acceptors, is compared to that shown by the unsubstituted halobenzenes (PhX, X = F, Cl, Br, I). The presence of pi and sigma radical anions was inspected as well as the intramolecular electron transfer (intra-ET) from the pi to the sigma surface, responsible for the dissociation of these intermediates. The profiles obtained with the B3LYP functional in the gas phase and in the presence of a polar solvent are in agreement with the spectroscopic evidence and with the experimentally observed reactivity of the compounds under study. The stability of the radical anion of p-nitrochlorobenzene and the adiabatic and endothermic nature of its dissociation are explained. The order of the rate constants for dissociation m-chloroacetophenone < p-chloroacetophenone is interpreted on the basis of the differences in the adiabatic character of the intra-ET of both isomers which is ascribed to the nodal properties of their SOMOs. In the halobenzene family, the electronic factors responsible for the intra-ET are analyzed. The stabilization of the sigma surface exerted by the different halogens and its effect on the rate constants for dissociation are explained.

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