title: Microbial efflux systems and inhibitors: approaches to drug discovery and the challenge of clinical implementation.
abstract: 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.
authors.affiliation: Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, NM, USA ; Department of Pathology, Faculty of Medicine, National & Kapodistrian University of Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Kourtesi
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Ball
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Huang
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Jachak
authors.forename: D Mariano A
authors.initials: DM
authors.lastname: Vera
authors.forename: Proma
authors.initials: P
authors.lastname: Khondkar
authors.forename: Simon
authors.initials: S
authors.lastname: Gibbons
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hamblin
authors.forename: George P
authors.initials: GP
authors.lastname: Tegos
keywords: Antimicrobial resistance; biofilms; dual action antimicrobials; multidrug efflux systems; natural efflux pump inhibitors; photo inactivation; virulence.