title: Microbial efflux pump inhibition: tactics and strategies.
abstract: Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs.
authors.affiliation: Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA. gtegos@salud.unm.edu
authors.forename: George P
authors.initials: GP
authors.lastname: Tegos
authors.forename: Mark
authors.initials: M
authors.lastname: Haynes
authors.forename: J Jacob
authors.initials: JJ
authors.lastname: Strouse
authors.forename: Mohiuddin Md T
authors.initials: MM
authors.lastname: Khan
authors.forename: Cristian G
authors.initials: CG
authors.lastname: Bologa
authors.forename: Tudor I
authors.initials: TI
authors.lastname: Oprea
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D015195:Drug Design; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D026901:Membrane Transport Proteins