Acquired antibiotic resistance is that which evolves in populations of susceptible commensal and pathogenic bacteria colonizing and infecting hosts that are under antibiotic treatment or prophylaxis. Acquired antibiotic resistance can result in treatment failure and contribute to transmissible or primary antibiotic resistance. The research proposed in this application will be devoted to understanding, in a quantitative and predictive way, the genetic, bacterial, host factors and population dynamic processes responsible for the evolution of acquired resistance in populations of bacteria infecting uncompromised mammals treated with single and multiple antibiotics. Towards this end, we will develop and analyze the properties of mathematical and computer simulation models of the within-host population dynamics of antibiotic treatment and the evolution of resistance and perform in vitro and in vivo (laboratory mouse) experiments with a capsulated E. coli (018:K1 :H7). In these experiments, we will estimate the parameters of these models, evaluate the reality of the assumptions behind their construction and test the validity of the predictions made from the analysis of their properties. The goals of this investigation are to; (1) Elucidate the conditions (dosage levels and treatment regimes) under which selection will favor the evolution of resistance in uncompromised mammals infected with antibiotic susceptible bacteria and treated with single antibiotics, multiple antibiotics and antibiotics for which clinical resistance requires multiple mutations. (2) Evaluate the contribution of post antibiotic effects (delays in the resumption of normal growth of antibiotic exposed bacteria after antibiotics are no longer at inhibitory concentrations) to the evolution of acquired resistance in populations of bacteria infecting antibiotic treated mammals. (3) Determine the contribution of elevated mutation rates to evolution acquired antibiotic resistance and the conditions under which antibiotic-mediated selection will result in the evolution of genes that augment mutation rates, mutator genes. The proposed research directed at these goals is in part, motivated by an academic interest in the mechanisms of adaptive evolution in bacteria. This research is also motivated by its direct utility to the health sciences and, in particular, to facilitate the design and evaluation of clinically effective antibiotic treatment protocols that minimize the likelihood of acquired antibiotic resistance evolving in the target population of bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040662-07
Application #
7059909
Study Section
Genetics Study Section (GEN)
Program Officer
Korpela, Jukka K
Project Start
1997-08-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
7
Fiscal Year
2006
Total Cost
$186,755
Indirect Cost
Name
Emory University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Margolis, Elisa; Yates, Andrew; Levin, Bruce R (2010) The ecology of nasal colonization of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus: the role of competition and interactions with host's immune response. BMC Microbiol 10:59
Haber, Michael; Levin, Bruce R; Kramarz, Piotr (2010) Antibiotic control of antibiotic resistance in hospitals: a simulation study. BMC Infect Dis 10:254
Wei, Yan; Ocampo, Paolo; Levin, Bruce R (2010) An experimental study of the population and evolutionary dynamics of Vibrio cholerae O1 and the bacteriophage JSF4. Proc Biol Sci 277:3247-54
Levin, Bruce R; Cornejo, Omar E (2009) The population and evolutionary dynamics of homologous gene recombination in bacterial populations. PLoS Genet 5:e1000601
Handel, Andreas; Margolis, Elisa; Levin, Bruce R (2009) Exploring the role of the immune response in preventing antibiotic resistance. J Theor Biol 256:655-62
Udekwu, Klas I; Parrish, Nicholas; Ankomah, Peter et al. (2009) Functional relationship between bacterial cell density and the efficacy of antibiotics. J Antimicrob Chemother 63:745-57
Cornejo, Omar E; Rozen, Daniel E; May, Robert M et al. (2009) Oscillations in continuous culture populations of Streptococcus pneumoniae: population dynamics and the evolution of clonal suicide. Proc Biol Sci 276:999-1008
Margolis, Elisa (2009) Hydrogen peroxide-mediated interference competition by Streptococcus pneumoniae has no significant effect on Staphylococcus aureus nasal colonization of neonatal rats. J Bacteriol 191:571-5
Johnsen, P J; Dubnau, D; Levin, B R (2009) Episodic selection and the maintenance of competence and natural transformation in Bacillus subtilis. Genetics 181:1521-33
Lemonnier, Marc; Levin, Bruce R; Romeo, Tony et al. (2008) The evolution of contact-dependent inhibition in non-growing populations of Escherichia coli. Proc Biol Sci 275:3-10

Showing the most recent 10 out of 26 publications