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MefA-mediated macrolide resistance i...

Turkson, Nicole Yamoah.

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MefA-mediated macrolide resistance in group A streptococci: The search for efflux pump inhibitors from marine natural products.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	MefA-mediated macrolide resistance in group A streptococci: The search for efflux pump inhibitors from marine natural products./
Author:	Turkson, Nicole Yamoah.
Description:	129 p.
Notes:	Adviser: William H. Fenical.
Contained By:	Dissertation Abstracts International68-01B.
Subject:	Biology, Microbiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3249663

MefA-mediated macrolide resistance in group A streptococci: The search for efflux pump inhibitors from marine natural products.
Turkson, Nicole Yamoah.

MefA-mediated macrolide resistance in group A streptococci: The search for efflux pump inhibitors from marine natural products. - 129 p.

Adviser: William H. Fenical.

Thesis (Ph.D.)--University of California, San Diego, 2007.

Efflux pumps are a detoxification mechanism widely distributed in biological systems. Their ability to extrude a broad range of pharmaceutical agents intended to treat infectious diseases makes them a formidable obstacle to effective treatment. Overuse, misuse and abuse of antibiotics throughout much of the world have led to the emergence of bacterial strains against which current therapies are becoming increasingly ineffective. The MefA pump is encoded by the mefA gene and confers resistance to 14- and 15-membered macrolide antibiotics (e.g. erythromycin, azithromycin) in Streptococcus pyogenes (Group A Streptococcus) and Streptococcus pneumoniae. A compound that blocks, or inhibits the action of this efflux pump could restore sensitivity of these bacteria to this important family of antibiotics. In this study, attention is turned toward secondary metabolites of marine origin as sources of novel bioactive compounds. An assay was developed to screen both crude extracts and pure compound samples for their ability to restore sensitivity of a mefA(+) strain of GAS to erythromycin. Parallel screens were performed using a serotype matched mefA(-) strain to control for independent antimicrobial activity. Several extracts were identified that reversed MefA-mediated erythromycin resistance, and these were fractionated using HPLC and subjected to various analytical techniques including mass spectrometry, UV spectroscopy and NMR spectroscopy to isolate the bioactive compounds and determine their chemical structures. Identification of a specific MefA inhibitor can serve as a lead point for rational design of novel antimicrobial agents to combat bacterial resistance mediated by drug efflux pumps. Additional molecular studies involve targeted mutagenesis and heterologous expression of mefA to determine its contribution to GAS host cell interactions, invasiveness and intracellular survival.Subjects--Topical Terms:

1017734
Biology, Microbiology.

MefA-mediated macrolide resistance in group A streptococci: The search for efflux pump inhibitors from marine natural products.
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035 $a (UMI)AAI3249663
035 $a AAI3249663
040 $a UMI $c UMI
100 1 $a Turkson, Nicole Yamoah. $3 1263306
245 1 0 $a MefA-mediated macrolide resistance in group A streptococci: The search for efflux pump inhibitors from marine natural products.
300 $a 129 p.
500 $a Adviser: William H. Fenical.
500 $a Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0132.
502 $a Thesis (Ph.D.)--University of California, San Diego, 2007.
520 $a Efflux pumps are a detoxification mechanism widely distributed in biological systems. Their ability to extrude a broad range of pharmaceutical agents intended to treat infectious diseases makes them a formidable obstacle to effective treatment. Overuse, misuse and abuse of antibiotics throughout much of the world have led to the emergence of bacterial strains against which current therapies are becoming increasingly ineffective. The MefA pump is encoded by the mefA gene and confers resistance to 14- and 15-membered macrolide antibiotics (e.g. erythromycin, azithromycin) in Streptococcus pyogenes (Group A Streptococcus) and Streptococcus pneumoniae. A compound that blocks, or inhibits the action of this efflux pump could restore sensitivity of these bacteria to this important family of antibiotics. In this study, attention is turned toward secondary metabolites of marine origin as sources of novel bioactive compounds. An assay was developed to screen both crude extracts and pure compound samples for their ability to restore sensitivity of a mefA(+) strain of GAS to erythromycin. Parallel screens were performed using a serotype matched mefA(-) strain to control for independent antimicrobial activity. Several extracts were identified that reversed MefA-mediated erythromycin resistance, and these were fractionated using HPLC and subjected to various analytical techniques including mass spectrometry, UV spectroscopy and NMR spectroscopy to isolate the bioactive compounds and determine their chemical structures. Identification of a specific MefA inhibitor can serve as a lead point for rational design of novel antimicrobial agents to combat bacterial resistance mediated by drug efflux pumps. Additional molecular studies involve targeted mutagenesis and heterologous expression of mefA to determine its contribution to GAS host cell interactions, invasiveness and intracellular survival.
590 $a School code: 0033.
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Oceanography. $3 783691
650 4 $a Chemistry, Pharmaceutical. $3 550957
690 $a 0410
690 $a 0416
690 $a 0491
710 2 $a University of California, San Diego. $3 1018093
773 0 $t Dissertation Abstracts International $g 68-01B.
790 $a 0033
790 1 0 $a Fenical, William H., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3249663