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 #
4R37AI023988-25
Application #
8391770
Study Section
Special Emphasis Panel (NSS)
Program Officer
Huntley, Clayton C
Project Start
1986-09-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
25
Fiscal Year
2013
Total Cost
$383,778
Indirect Cost
$156,547
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Villet, Regis A; Truong-Bolduc, Que Chi; Wang, Yin et al. (2014) Regulation of expression of abcA and its response to environmental conditions. J Bacteriol 196:1532-9
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
Truong-Bolduc, Que Chi; Bolduc, Gilles R; Okumura, Ryo et al. (2011) Implication of the NorB efflux pump in the adaptation of Staphylococcus aureus to growth at acid pH and in resistance to moxifloxacin. Antimicrob Agents Chemother 55:3214-9
Didier, Jean-Philippe; Villet, Regis; Huggler, Elzbieta et al. (2011) Impact of ciprofloxacin exposure on Staphylococcus aureus genomic alterations linked with emergence of rifampin resistance. Antimicrob Agents Chemother 55:1946-52
Truong-Bolduc, Q C; Dunman, P M; Eidem, T et al. (2011) Transcriptional profiling analysis of the global regulator NorG, a GntR-like protein of Staphylococcus aureus. J Bacteriol 193:6207-14
Truong-Bolduc, Que Chi; Hooper, David C (2010) Phosphorylation of MgrA and its effect on expression of the NorA and NorB efflux pumps of Staphylococcus aureus. J Bacteriol 192:2525-34
Jacoby, George; Cattoir, Vincent; Hooper, David et al. (2008) qnr Gene nomenclature. Antimicrob Agents Chemother 52:2297-9
Truong-Bolduc, Que Chi; Ding, Yanpeng; Hooper, David C (2008) Posttranslational modification influences the effects of MgrA on norA expression in Staphylococcus aureus. J Bacteriol 190:7375-81