Researchers Sequence the Ubiquitous Pseudomonas aeruginosa

Data derived from the Science Watch/Hot Papers database and the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. Pseudomonas aeruginosa gets around. The bacterium thrives in soil and marshes, on marine coasts, and in plant and animal tissues. Of particular interest is its occasional, but often devastating, inhabitation of the human environment. It is an important cause of bacteremia associated with burn wounds and with hospital-acquired pneumonia in patients on respirators. It is the microbe that most commonly infects the lungs of patients with cystic fibrosis. Aside from its adaptability, P. aeruginosa is also famous for its natural drug resistance. In general, relatively high doses of aminoglycosides, such as tobramycin, extended-spectrum beta-lactams, and ciprofloxacin, are required to eradicate this organism. P. aeruginosa's genome is one of the largest and most complicated bacterial genomes known, with an estimated 6.3 million base pairs and 5,570 open reading frames, giving this prokaryote a complexity on par with simple eukaryotes. AN UNUSUAL COLLABORATION P. aeruginosa's pathogenicity has made it a marked microbe, and this Hot Paper describes its genetic sequence as obtained by a large, interdisciplinary team comprising researchers from Pathogenesis (now part of Emeryville, Calif.-based Chiron), the University of Washington Genome Center, Seattle, and others, with financial assistance from the Cystic Fibrosis Foundation.1 "I think [this collaboration] is quite unusual," says Stephen Lory, who was part of the University of Washington team and is now a professor of microbiology and molecular genetics at Harvard Medical School. "Since the effort was shared by three entities with different goals, a compromise on the data release was reached, which assured that the sequence information became a resource for the research community and not just one company or one group of investigators." Photo: Courtesy of Stephen Lory Stephen Lory After completing the shotgun sequence, one of the first things the researchers wanted to know was whether the size and complexity of the bacteria's genome had anything to do with its remarkable adaptability and inherent drug resistance. Predictably, the answer was yes in both cases. A computational analysis revealed that the genome had a "rather striking" number of nutrient transporters, allowing it to subsist on a variety of organic molecules such as carbohydrates. Nutrient use is "often a limiting factor for where bacteria can live," says Lory. P. aeruginosa's large size allows it to carry a variety of other useful genes as well. Previous work had already identified four drug efflux systems,2,3 but the analysis predicted that the bacteria's genome codes for perhaps a dozen more. Finally, to coordinate this arsenal of survival genes, the team found that P. aeruginosa carries an unusually high number of regulatory genes that determine which should be expressed and when. Lory notes, "It is a very sophisticated organism, which is probably why it thrives in many environments." THE PRACTICAL IMPACT One of the immediate results of the paper was a microarray initiative that quickly resulted in a DNA chip produced by Affymetrix, of Santa Clara, Calif. Like the genome project, Affymetrix's chip also gained financial support from the Cystic Fibrosis Foundation. That support made the chip relatively inexpensive, and because of it "we understand much more about what genes are expressed [and] under what variety of conditions that are relevant to disease," says Lory. The unusual nature of the project's funding also has made it more generally available and useful than that of most other genome projects, according to Lory. "This came with a very strong annotation site (www.pseudomonas.com/original.html) ... which had many users even before the paper was published." It was so useful, in fact, that the "use of the site probably dropped after [the genome] was published because those who were really interested had already mined the data." One researcher who took advantage of the early data release was Peter Greenberg, University of Iowa. He and his team identified 39 genes and a signaling network that responds to quorum sensing in P. aeruginosa.4 And, after the Hot Paper's publication, Lory collaborated on another project that identified genes that were differentially expressed as a result of biofilm formation, a process that may play a role in the pathogenesis of infection in patients with cystic fibrosis.5 The paper likely received as much attention as it did because the bacteria's large and complex genome attracted researchers from a variety of fields, from medical microbiology, to environmental microbiology, to evolutionary microbiology. "People working on other biological systems often find something [analogous] in Pseudomonas," notes Lory. "There is biology coming from a lot of different angles." Jim Kling (jkling@nasw.org) is a freelance writer in Washington, DC. References 1. C.K. Stover, X.Q. Pham, A.L. Erwin, S.D. Mizoguchi, et al., "Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen," Nature, 406:959-64, Aug. 31, 2000. (Cited in 260 papers) 2. S. Westbrock-Wadman et al., "Characterization of a Pseudomonas aeruginosa efflux pump contributing to aminoglycoside impermeability," Antimicrobial Agents and Chemotherapy, 43:2975-83, 1999. 3. H. Nikaido et al., "Antibiotic resistance caused by gram-negative multidrug efflux pumps," Clinical Infectious Diseases, 27:532-41, 1998. 4. M. Whiteley et al., "Identification of genes controlled by quorum sensing in Pseudomonas aeruginosa," Proceedings of the National Academy of Sciences, 96:13904-9, 1999. 5. M. Whiteley et al., "Gene expression in Pseudomonas aerugionosa biofilms," Nature, 413:860-64, 2001.

Researchers Sequence the Ubiquitous Pseudomonas aeruginosa

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