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      Farnesol, a Potential Efflux Pump Inhibitor in Mycobacterium smegmatis

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          Abstract

          The active multidrug efflux pump (EP) has been described as one of the mechanisms involved in the natural drug resistance of bacteria, such as mycobacteria. As a result, the development of efflux pumps inhibitors (EPIs) is an important topic. In this study, a checkerboard synergy assay indicated that farnesol both decreased the minimum inhibitory concentration (MIC) of ethidium bromide (EtBr) 8-fold against Mycobacterium smegmatis ( M. smegmatis) mc 2155 ATCC 700084 when incorporated at a concentration of 32 μg/mL (FICI = 0.625) and decreased MIC 4-fold at 16 μg/mL (FICI = 0.375). Farnesol also showed synergism when combined with rifampicin. A real-time 96-well plate fluorometric method was used to assess the ability of farnesol to inhibit EPs in comparison withfour positive EPIs: chlorpromazine, reserpine, verapamil, and carbonyl cyanide m-chlorophenylhydrazone (CCCP). Farnesol significantly enhanced the accumulation of EtBr and decreased the efflux of EtBr in M. smegmatis; these results suggest that farnesol acts as an inhibitor of mycobacterial efflux pumps.

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          Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria.

          Laura Piddock (2006)
          Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed.
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            Bacterial efflux pump inhibitors from natural sources.

            Michael Stavri, Laura Piddock, Simon Gibbons (2007)
            The rapid spread of bacteria expressing multidrug resistance (MDR) has necessitated the discovery of new antibacterials and resistance-modifying agents. Since the initial discovery of bacterial efflux pumps in the 1980s, many have been characterized in community- and hospital-acquired Gram-positive and Gram-negative pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and, more recently, in mycobacteria. Efflux pumps are able to extrude structurally diverse compounds, including antibiotics used in a clinical setting; the latter are rendered therapeutically ineffective. Antibiotic resistance can develop rapidly through changes in the expression of efflux pumps, including changes to some antibiotics considered to be drugs of last resort. It is therefore imperative that new antibiotics, resistance-modifying agents and, more specifically, efflux pump inhibitors (EPIs) are characterized. The use of bacterial resistance modifiers such as EPIs could facilitate the re-introduction of therapeutically ineffective antibiotics back into clinical use such as ciprofloxacin and might even suppress the emergence of MDR strains. Here we review the literature on bacterial EPIs derived from natural sources, primarily those from plants. The resistance-modifying activities of many new chemical classes of EPIs warrant further studies to assess their potential as leads for clinical development.
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              Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility.

              M A Jabra-Rizk, T F Meiller, C JAMES … (2006)
              Staphylococcus aureus is among the leading pathogens causing bloodstream infections able to form biofilms on host tissue and indwelling medical devices and to persist and cause disease. Infections caused by S. aureus are becoming more difficult to treat because of increasing resistance to antibiotics. In a biofilm environment particularly, microbes exhibit enhanced resistance to antimicrobial agents. Recently, farnesol was described as a quorum-sensing molecule with possible antimicrobial properties. In this study, the effect of farnesol on methicillin-resistant and -susceptible strains of S. aureus was investigated. With viability assays, biofilm formation assessment, and ethidium bromide uptake testing, farnesol was shown to inhibit biofilm formation and compromise cell membrane integrity. The ability of farnesol to sensitize S. aureus to antimicrobials was assessed by agar disk diffusion and broth microdilution methods. For both strains of staphylococci, farnesol was only able to reverse resistance at a high concentration (150 microM). However, it was very successful at enhancing the antimicrobial efficacy of all of the antibiotics to which the strains were somewhat susceptible. Therefore, synergy testing of farnesol and gentamicin was performed with static biofilms exposed to various concentrations of both agents. Plate counts of harvested biofilm cells at 0, 4, and 24 h posttreatment indicated that the combined effect of gentamicin at 2.5 times the MIC and farnesol at 100 microM (22 microg/ml) was able to reduce bacterial populations by more than 2 log units, demonstrating synergy between the two antimicrobial agents. This observed sensitization of resistant strains to antimicrobials and the observed synergistic effect with gentamicin indicate a potential application for farnesol as an adjuvant therapeutic agent for the prevention of biofilm-related infections and promotion of drug resistance reversal.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 29 October 2010
                Publication date Collection: November 2010
                Volume: 15
                Issue: 11
                Pages: 7750-7762
                Affiliations
                [1 ]Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, 130062, China
                [2 ]Key and Open Laboratory of Veterinary Pharmaceutical Engineering, Lanzhou Institute of Animal Science and Veterinary Pharmaceutics, Chinese Academy of Agricultural Sciences, Lanzhou, 730050, China
                [3 ]Laboratory of Nutrition and Functional Food, Jilin University, Changchun, 130062, China
                [4 ]The First Hospital of Jilin University, Jilin University, Changchun, 130021, China
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ] Authors to whom correspondence should be addressed; E-Mails: yulu225@ 123456yahoo.com.cn (L.Y.); wxp33@ 123456yahoo.com (X.-P.W.); Tel.: +86-431-87836713(L.Y.); +86-431-87836713 (X.-P.W.); Fax: +86-431-87836160 (L.Y.); +86-431-87836160 (X.-P.W.).
                Article
                Publisher ID: molecules-15-07750
                DOI: 10.3390/molecules15117750
                PMC ID: 6259160
                PubMed ID: 21042264
                SO-VID: 05c7f16c-c24e-46d6-ba06-a37f8ed43157
                Copyright © © 2010 by the authors;
                License:

                licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 01 September 2010
                Date revision received : 02 October 2010
                Date accepted : 25 October 2010
                Categories
                Subject: Article

                Keywords: farnesol,inhibitor,efflux pump,mycobacterium smegmatis
                Data availability:
                Keywords: farnesol, inhibitor, efflux pump, mycobacterium smegmatis

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