Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation
Christina Kourtesi 1, 2, Anthony R Ball 3, Ying-Ying Huang 4, 5, Sanjay M Jachak 6, D Mariano A Vera 7, Proma Khondkar 8, Simon Gibbons 8, Michael R Hamblin 4, 5, 9, George P Tegos*, 1, 4, 5, 10
1 Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, NM, USA
2 Department of Pathology, Faculty of Medicine, National & Kapodistrian University of Athens, Greece
3 Department of Microbiology, Toxikon Corp. Bedford, MA 01730, USA
4 Department of Dermatology, Harvard Medical School, Boston MA, USA
5 Wellman Center for Photomedicine, Massachusetts General Hospital, Boston MA, USA
6 Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, SAS Nagar, Punjab, India
7 Department of Chemistry, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 3350 – 7600- Mar del Plata, Argentina
8 Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London WC1N 1AX, UK
9 Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA
10 Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA
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.
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* Address correspondence to this author at the Department of Pathology School of Medicine & Center for Molecular Discovery University of New Mexico, UNM Health Sciences Center 2325 Camino de Salud, CRF 217A MSC 07-4025 Albuquerque, NM 87131, USA; Tel: 505-272-1608;
Fax: 505-272-6995; E-mail: firstname.lastname@example.org