Department of microbiology and molecular genetics
Faculty profile
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Anthony J. Zuccarelli 11021 Campus Street |
- PhD (biophysics) - California Institute of Technology, Pasadena, California - 1974
- Postdoctoral fellow, American Cancer Society, University of Constance, Germany, 1974-1976
- Director, medical scientist program (MD, PhD)
- Director, summer undergraduate research program
- Current research interests
- Recent publications
- Teaching
Areas of research
Genetic polymorphisms in Staphylococcus aureus, molecular typing of pathogenic microorganisms, genetic determinants of bacterial virulence, molecular genetics of bacteriophages.
Current research projects
Many microorganisms have become resistant to antibiotics. Multidrug resistance is so common in some pathogens that few options remain for effective treatment. Research in my laboratory focuses on discovering the genetic mechanisms that create plasmids containing antibiotic resistance genes and the impact of those genes on the fitness of the host strains.
The genes responsible for resistance have several origins. Most are foreign genes imported on plasmids from other resistant microorganisms. Some are the result simple mutations occurring in preexisting bacterial genes. On rare occasions the reshuffling of old gene segments may create new genes that confer resistance.
In almost every case, however, resistance comes with an energetic price tag. Energy is needed to replicate the extra genes, to synthesize the encoded proteins and to support their biochemical activities. In some cases, resistance reduces the efficiency of an essential biochemical process, like DNA, RNA or protein synthesis. The cell must expend additional energy to compensate for these deficiencies.
Our laboratory is examining the hypothesis that resistant bacteria are at a selective disadvantage in the absence of antibiotics. The counter-proposal, that resistant organisms have the same or greater fitness than their sensitive counterparts, has also been proposed, based upon a few individual observations.
Discriminating between these alternatives has significant practical implications. If antibiotic resistance reduces fitness, then competition between sensitive and resistant organisms in the absence of antibiotics will favor the sensitive organism. Resistant organisms should decline relative to their sensitive counterparts in the absence of antibiotics. In health care settings, if an particular antibiotic with poor clinical effectiveness is removed from the formulary because of wide-spread resistance, the hypothesis predicts that bacterial populations will gradually drift back toward sensitivity. After a time the effectiveness of the antibiotic may be restored. The hypothesis also suggests that it would be beneficial to purposely replenish a patient's sensitive bacterial flora after antibiotic therapy. Competition between the introduced sensitive microorganisms and resistant forms remaining after antibiotic treatment will reduce and eventually eliminate the resistant representatives. If substantiated, both approaches have the potential for decreasing the incidence of resistant infections, increasing the effectiveness of subsequent treatments and reducing their cost.
In its simplest form, our experimental approach is to measure the relative growth of bacterial strains that differ only in their resistance to an antibiotic. Isogenic strains can be constructed by introducing an antibiotic resistance gene into a sensitive microorganism. The unmodified sensitive strain and its resistant derivative are inoculated together into a growth medium at a convenient starting ratio. Changes in the ratio can be monitored periodically during their subsequent growth. A simple calculation shows that a 0.01% difference in relative growth rates will generate a measurable population shift in 100 generations. That can be achieved in a few days with bacteria that have a doubling time of about 30 minutes.
We have previously analyzed a large collection of Staphylococcus aureus isolates obtained from infected patients. From them we have isolated many plasmids characterized by size, resistance genes and locations of restriction enzyme cleavage sites. Using this resource we created pairs of strains that differ in their antibiotic resistance by introducing plasmids individually into sensitive laboratory strains. When the pair are grown together the population ratio shifts dramatically towards sensitivity, in most cases. Our current work is aimed at identifying the individual plasmid genes directly responsible for this observation. We are also examining the possibility that bacteria can compensate for the energetic burden of resistance by adjusting other aspects of their metabolism to achieve a net growth rate equivalent to that of sensitive cells.
Click on the 
symbol beside the reference to read the corresponding abstract.
16. Sarmiento, D., G. Harding, B. Barton & A. J. Zuccarelli. 1999. Molecular relationships among plasmids from methicillin-resistant Staphylococcus aureus. (in preparation).
15. Sarmiento, D., G. Harding & A.J. Zuccarelli. 1999. A multimeric megaplasmid in methicillin-resistant Straphylococcus aureus. (in preparation).
14. Barton, B., G. Harding & A.J. Zuccarelli. 1999. Genomic polymorphisms in clinical isolates of methicillin-resistant Staphylococcus aureus. (in preparation).
13. Rebbapragada, A., M.S. Johnson, G.P. Harding, A.J. Zuccarelli, H. Fletcher, I.B. Zhulin, B.L. . Taylor. 1997. A novel sensor, Aer, and the serine chemoreceptor Tsr independently sense intracellular energy levels and transduce oxygen, redox, and energy signals for Escherichia coli behavior. Proc. Nat. Acad. Sci. 94:10541-10546.
12. Barton, B., G. Harding, D. Sarmiento, & A.J. Zuccarelli. 1995. A general method for detecting and sizing large plasmids. Analytical Biochemistry 226:235-240.
11. Wilkins, D.L., P. Chung, P. Tsuchiya & A.J. Zuccarelli. 1994. Microbiologic evaluation of heat and chemical sterilization systems. Ophthalmic Surgery 25:690-690.
10. Bullas, L.R., A.R. Mostaghimi, J.J. Arensdorf, P.T. Rajadas & A.J. Zuccarelli. 1991. Salmonella phage PSP3 is a member of the P2-like phage group. Virol. 185:918-921.
9. Zuccarelli, A.J., I. Roy, G. Harding & J. Couperus. 1990. Diversity and stability of plasmids in methicillin resistant Staphylococcus aureus. Journal of Clinical Microbiology. 28:97-102.
8. Pollman, M. & A.J. Zuccarelli. 1989. Rapid isolation of high molecular weight DNA from agarose gels. Analytical Biochemistry. 181:12-17.
7. Zuccarelli, A.J., R.M. Benbow & R.L. Sinsheimer. 1976. Synthesis of the first complementary strand of fX174. Journal of Molecular Biology. 106:375-402.
6. Benbow, R.M., A.J. Zuccarelli & R.L. Sinsheimer. 1975. Recombinant DNA molecules of bacteriophage fX174. Proceeding of the National Academy of Sciences USA. 72:235-239.
5. Benbow, R.M., A.J. Zuccarelli & R.L. Sinsheimer. 1974. A role for single-stranded breaks in bacteriophage fX174 genetic recombination. Journal of Molecular Biology. 88:629-651.
4. Benbow, R.M., A.J. Zuccarelli, A.J. Shafer & R.L. Sinsheimer. 1974. Exchange of parental DNA during genetic recombination in bacteriophage fX174. In Mechanisms in Recombination (Grell, R.F., ed.) pp.3-18, Plenum, New York.
3. Benbow, R.M., A.J. Zuccarelli, G.C. Davis & R.L. Sinsheimer. 1974. Genetic recombination in bacteriophage fX174. Journal of Virology. 13:898-907.
2. Zuccarelli, A.J., R.M. Benbow & Sinsheimer. 1972. Deletion mutants of bacteriophage fX174. Proceedings of the National Academy of Sciences, USA. 69:1905-1910.
1. Bullas, L.R., A.J. Zuccarelli & R.L. Nutter. 1967. Ageing effect on phage particles leading to an increase in burst size. Nature 216:1308.
Cell and Molecular Biology - CMBL502, lecturer.
Biochemistry and Molecular Genetics - MDCJ535, 536, 537, co-coordinator.
Clinical Correlates - CMBL511, 512, 513, coordinator.
Medical Microbiology - MICR511, small group instruction in clinical microbiology laboratory techniques and patient-oriented problem-solving.
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