Professor of Microbiology & Immunology
Ph.D., University of Rochester

Pathogenesis of Aggregatibacter actinomycetemcomitans; molecular genetics of promiscuous bacterial plasmids

Bacterial adherence. The Gram-negative bacterium Aggregatibacter actinomycetemcomitans is the etiologic agent for localized aggressive periodontitis (LAP), a particularly destructive disease in adolescents. Fresh clinical isolates of A. actinomycetemcomitans form extremely tenacious biofilms, a property critical for colonization of teeth. Using molecular genetic approaches, we have identified a cluster of tad (tight adherence) genes required for tight adherence to surfaces. Remarkably similar tad-like loci were subsequently found in the genome sequences of a wide variety of Gram-negative and Gram-positive Bacteria, including many significant pathogens, and in Archaea. We suggest that tad loci in other organisms are likely to be important for colonization in a variety of environmental niches. Our work is directed to understanding the mechanisms of expression and regulation of the genes of the tad locus; and to determining the locations, interactions, and molecular functions of the gene products in secretion and fibril assembly. Because of the widespread nature of the tad loci, these studies may also help to identify new targets for development of antibiotics.

Promiscuous antibiotic-resistance plasmids. The evolution, spread, and replication of antibiotic resistant plasmids in bacteria have resulted in a serious worldwide problem that is threatening to undermine the treatment of bacterial infectious disease. We are investigating the extraordinary IncP family of self-transmissible, highly promiscuous, antibiotic resistant plasmids that are capable of two remarkable behaviors: (1) conjugal transfer to virtually any bacterial species, and (2) efficient replication and stable inheritance in a wide variety of Gram-negative bacteria. Our work has revealed the existence of a novel plasmid regulon (the kor regulon) whose multiple operons encode a distinctive active partition system for DNA segregation and novel genes for plasmid maintenance in different hosts. We are using a combination of genetic and biochemical approaches to determine the molecular functions of these gene products in diverse bacterial species.

Colonization and virulence of the human bacterial pathogen Aggregatibacter actinomycetemcomitans (with Dan Fine, Univ. of Medicine & Dentistry of New Jersey).

Evolution of the Widespread Colonization Island in bacteria (with Rob DeSalle, American Museum of Natural History).

Gene transfer to mammalian mitochondria (with Eric Schon, Dept. of Genetics, Columbia University).

Nucleotide sequence of bacteriophage ΦAa of Aggregatibacter actinomycetemcomitans (with Roy Stevens, Temple Univ.; Rob DeSalle, AMNH; and Dan Fine, UMDNJ).

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1. Lim, Y.M., de Groof, A.J., Bhattacharjee, M.K., Figurski, D.H. and Schon, E.A. (2008) Bacterial conjugation in the cytoplasm of mouse cells. Infect. Immun. 76: 5110-5119.
2. Kram, K.E., Hovel-Miner, G.A., Tomich, M. and Figurski, D.H. (2008) Transcriptional regulation of the tad locus in Aggregatibacter actinomycetemcomitans: a termination cascade. J. Bacteriol. 190: 3859-3868.
3. Clock, S.A., Planet, P.J., Perez, B.A. and Figurski, D.H. (2008) Outer membrane components of the Tad (tight adherence) secreton of Aggregatibacter actinomycetemcomitans. J. Bacteriol. 190: 980-990.
4. Bhattacharjee, M.K., Fine, D.H. and Figurski, D.H. (2007) tfoX (sxy)-dependent transformation of Aggregatibacter (Actinobacillus) actinomycetemcomitans. Gene. 399: 53-64.
5. Tomich, M., Planet, P.J. and Figurski, D.H. (2007) The tad locus: postcards from the widespread colonization island. Nat. Rev. Microbiol. 5: 363-375. Review.
6. Tomich, M., Fine, D.H. and Figurski, D.H. (2006) The TadV protein of Actinobacillus actinomycetemcomitans is a novel aspartic acid prepilin peptidase required for maturation of the Flp1 pilin and TadE and TadF pseudopilins. J. Bacteriol. 188: 6899-6914.
7. Perez, B.A., Planet, P.J., Kachlany, S.C., Tomich, M., Fine, D.H. and Figurski, D.H. (2006) Genetic analysis of the requirement for flp-2, tadV, and rcpB in Actinobacillus actinomycetemcomitans biofilm formation. J. Bacteriol. 2006 188: 6361-6375.
8. Planet, P.J., Kachlany, S.C., Fine, D.H., DeSalle, R. and Figurski, D.H. (2003) The Widespread Colonization Island (WCI) of Actinobacillus actinomycetemcomitans. Nature Genetics 34: 193-198.
9. Schreiner, H.C., Sinatra, K., Kaplan, J.B., Furgang, D., Kachlany, S.C., Planet, P.J., Perez, B.A., Figurski, D.H. and Fine, D.H. (2003) Tight adherence genes of Actinobacillus actinomycetemcomitans are required for virulence in a rat model. Proc. Natl. Acad. Sci. USA 100: 7295-7300.
10. Sarkar, I.N,. Planet, P.J., Bael, T.E., Stanley, S.E., Siddall, M., DeSalle, R. and Figurski, D.H. (2002) Characteristic attributes in cancer microarrays. J. Biomedical Informatics 35: 111-122.
11. Siddique, A. and Figurski, D.H. (2002) Active partition gene incC of IncP plasmids is required for stable maintenance in a broad range of hosts. J. Bacteriol. 184: 1788-1793.
12. Bhattacharyya, A. and Figurski, D.H. (2001) A small protein-protein interaction domain common to KlcB and global regulators KorA and TrbA of promiscuous IncP plasmids. J. Mol. Biol. 310: 51-67.
13. Kachlany, S.C., Planet, P.J., DeSalle, R., Fine, D.H. and Figurski, D.H. (2001) Genes for tight adherence of Actinobacillus actinomycetemcomitans: from plaque to plague to pond scum. Trends Microbiol. 9: 429-437.