Bacterial efflux pumps can cause multidrug resistance when overexpressed, and mutational mechanisms of overexpression have involved an array of global regulators. In Staphylococcus aureus pumps NorA, NorB, and NorC can confer resistance to various quinolone antimicrobials along with chloramphenicol and some dyes. Pump Tet38 confers resistance to tetracyclines, and pump AbcA confers resistance to plactams with hydrophobic side-chains. Two global transcriptional regulators, MgrA and NorG, are known to have direct regulatory roles in the expression of various of these pumps. The work described below has focused on i) defining the regulatory mechanisms that control pump expression (including the complex interactions of various regulators), ii) determination of the role of pump expression in the adaptation of S. aureus to survival in an abscess, its most common cause of infection, iii) determination of the environmental signals that trigger pump expression, and iv) defining the natural substrates of these generally broad-spectrum pumps, for which antimicrobials may be incidental substrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI023988-26
Application #
8608992
Study Section
Special Emphasis Panel (NSS)
Program Officer
Huntley, Clayton C
Project Start
1986-09-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
26
Fiscal Year
2014
Total Cost
$391,592
Indirect Cost
$166,539
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Truong-Bolduc, Q C; Wang, Y; Chen, C et al. (2017) Transcriptional Regulator TetR21 Controls the Expression of the Staphylococcus aureus LmrS Efflux Pump. Antimicrob Agents Chemother 61:
Truong-Bolduc, Q C; Khan, N S; Vyas, J M et al. (2017) Tet38 Efflux Pump Affects Staphylococcus aureus Internalization by Epithelial Cells through Interaction with CD36 and Contributes to Bacterial Escape from Acidic and Nonacidic Phagolysosomes. Infect Immun 85:
Nakaminami, Hidemasa; Chen, Chunhui; Truong-Bolduc, Que Chi et al. (2017) Efflux Transporter of Siderophore Staphyloferrin A in Staphylococcus aureus Contributes to Bacterial Fitness in Abscesses and Epithelial Cells. Infect Immun 85:
Hooper, David C; Jacoby, George A (2016) Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance. Cold Spring Harb Perspect Med 6:
Hooper, David C; Jacoby, George A (2015) Mechanisms of drug resistance: quinolone resistance. Ann N Y Acad Sci 1354:12-31
Truong-Bolduc, Q C; Bolduc, G R; Medeiros, H et al. (2015) Role of the Tet38 Efflux Pump in Staphylococcus aureus Internalization and Survival in Epithelial Cells. Infect Immun 83:4362-72
Truong-Bolduc, Que Chi; Villet, Regis A; Estabrooks, Zoe A et al. (2014) Native efflux pumps contribute resistance to antimicrobials of skin and the ability of Staphylococcus aureus to colonize skin. J Infect Dis 209:1485-93
Kwak, Yee Gyung; Truong-Bolduc, Que Chi; Bin Kim, Hong et al. (2013) Association of norB overexpression and fluoroquinolone resistance in clinical isolates of Staphylococcus aureus from Korea. J Antimicrob Chemother 68:2766-72
Truong-Bolduc, Que Chi; Hsing, Liao Chun; Villet, Regis et al. (2012) Reduced aeration affects the expression of the NorB efflux pump of Staphylococcus aureus by posttranslational modification of MgrA. J Bacteriol 194:1823-34
Ding, Yanpeng; Fu, Yingmei; Lee, Jean C et al. (2012) Staphylococcus aureus NorD, a putative efflux pump coregulated with the Opp1 oligopeptide permease, contributes selectively to fitness in vivo. J Bacteriol 194:6586-93

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