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Faculty

Don B. Clewell

Emeritus Professor
Ph.D, Indiana University, 1967
dclewell@umich.edu




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Enterococcal plasmids, transposons, and antibiotic resistance

The work of our research group over many years has related generally to the emergence and dissemination of multiple antibiotic resistance in bacteria.  We have been interested in mobile genetic elements and have focused primarily on the phenomenon of conjugation as it relates to the intercellular transfer of plasmids and conjugative transposons in enterococci.  The enterococci normally inhabit the human intestine and are opportunistic pathogens often associated with bacteremia, urinary tract infections and infective endocarditis. They are among the three most common types of bacteria involved in nosocomial infections in the United States. 

A major part of our work has related to the identification and characterization of plasmids in Enterococcus faecalis that encode a mating response to peptide sex pheromones that are secreted by plasmid-free strains.  We have focused extensively on the plasmid pAD1 (encodes a hemolysin and UV-resistance) and more recently on other plasmids that relate to the significant emergence of vancomycin-resistance in enterococci.  Our work has dealt mainly with characterizing the molecular mechanisms involved in regulation of the mating (conjugative) response; however, we have also been interested in the chromosome-borne genes associated with pheromone biosynthesis.

Other research activities have dealt with specific antibiotic resistance genes and their association with transposons.  This has involved the identification and characterization of elements such as the conjugative transposons Tn916, Tn918 and Tn919 (encode resistance to tetracycline), as well as Tn917 (a transposon of the Tn3 family encoding resistance to erythromycin).

Finally, we have also engaged in studies of gene regulation in Streptococcus gordonii, an organism that is a common component of normal dental plaque.  This has related mainly to expression of a gene encoding the enzyme glucosyltransferase which is responsible for utilizing sucrose to generate polymers of glucose (glucan) that are involved in the ability of cells to accumulate on tooth surfaces. Regulation was found to involve a positive regulator Rgg, which has turned out to represent the “prototype” of a large family of regulator proteins in Gram-positive bacteria.

Selected Publications

Francia, M. V., and D. B. Clewell. 2002. Amplification of the tetracycline-resistance determinant of pAMa1 in Enterococcus faecalis requires a site specific recombination event involving relaxase. J. Bacteriol. 184:5187-5193.

Flannagan, S. E., J. W. Chow, S. M. Donabedian, W. J. Brown, M. B. Perri, M. J. Zervos, Y. Ozawa, and D. B. Clewell. 2003. Characterization of the plasmid content of an Enterococcus faecalis VRE isolated from a patient also colonized by a Staphylococcus aureus with a VanA phenotype. Antimicrob. Agents Chemoth. 47:3954-3959.

Weigel, L. M., D. B. Clewell, S. R. Gill, N. C. Clark, L. K. McDougal, S. E. Flannagan, J. F. Kolonay, J. Shetty, G. E. Killgore, and F. C. Tenover. 2003. Molecular analysis of a clinical isolate of Staphylococcus aureus with high-level resistance to vancomycin. Science 302:1569-1571.

Clewell, D. B. and M. V. Francia. 2004. Conjugation in Gram-positive bacteria.  pp 227-256 In : Funnell, B. (Ed.) Plasmid Biology. American Society for Microbiology, Washington, DC

Francia, M. V., S. Fujimoto, P. Tille, K. E. Weaver, and D. B. Clewell. 2004. Replication of Enterococcus faecalis pheromone-responding plasmid pAD1: location of the minimal replicon and oriV site and RepA involvement in initiation of replication. J. Bacteriol. 186: 5003-5016.

Ozawa, Y., E. H. De Boever, and D. B. Clewell. 2005. Enterococcus faecalis sex pheromone plasmid pAM373: analyses of TraA and evidence for its interaction with RpoB, Plasmid 54: 57-69.

Clewell, D. B.,2007. Properties of Enterococcus faecalis plasmid pAD1, a member of a widely disseminated family of pheromone-responding, conjugative, virulence elements encoding cytolysin. , Plasmid 58: 205-227.

Francia, M. V., K. E. Weaver, P. Goicoechea, P. Tille, and D. B. Clewell. 2007.  Characterization of an active partition system for the Enterococcus faecalis pheromone-responding plasmid pAD1.  J. Bacteriol. 189: 8546-8555.

Flannagan, S.E., D.B. Clewell, and C. M. Sedgley. 2008. A “retrocidal” plasmid in Enterococcus faecalis: passage and protection. Plasmid, 59: 217-230.

Vickerman, M. M., S. E. Flannagan, A. M. Jesionowski, K. A. Brossard, D. B. Clewell, C. M. Sedgley. 2010. A genetic determinant in Streptococcus gordonii Challis encodes a peptide with activity similar to enterococcal sex pheromone cAM373, which facilitates intergeneric DNA transfer. J. Bacteriol. 192: 2535-2545.

Hwang, Y-C, S. E. Flannagan, D. B. Clewell,, and C. M. Sedgley, C. M. 2011. Bacteriocin-related siblicide in clinical isolates of enterococci. Probiotics and Antimicrobial Proteins, 3:57-61.

Clewell, D. B. 2011. Tales of conjugation and sex pheromones. A plasmid and enterococcal odyssey. Mob. Genet. Elements, 1:38-54.

Francia, M. V., D. B. Clewell, F. de la Cruz, G. Moncalian. 2013. Catalytic domain of plasmid pAD1 relaxase TraX defines a group of relaxases related to restriction endonucleases. Proc Nat Acad Sci U. S. A. 110: 13606-13611.

Clewell, D. B. 2014. Antibiotic Resistance Plasmids in Bacteria. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0001491.pub3

Clewell, D. B., K. E. Weaver, G. M. Dunny, T. M. Coque, M. V. Francia, F. Hayes. 2014. Extrachromosomal and mobile elements in enterococci. Transmission, maintenance and epidemiology. 2014-. In: M. S. Gilmore, D. B. Clewell, Y. Ike, and N. Shankar (eds). Enterococci: From Commensals to Leading Causes of Drug Resistant Infection. Massachusetts Eye and Ear Infirmary. Boston (an open access book on the U.S. National Institutes of Health NCBI Bookshelf)