Nitric Oxide – A Newly Discovered Potential Target for Biofilm Control

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V. harveyi Can Spell! Image Source: Bonnie Bassler, Photo credit: Zachary Donnell

Eavesdropping on Bacteria

Bacteria chatter continuously and their words are chemical,” according to Bonnie Bassler, PhD, from the Howard Hughes Medical Institute and Princeton University in New Jersey, who spends most of her research time eavesdropping on bacteria and deciphering their languages.  “Not only can these cells talk with one another, they’re multilingual,” she says.

Three major bacterial languages have been extensively investigated: those used by Gram-negative cells and mediated by acylated homoserine lactone (AHL); the oligopeptides QS molecules Gram-positive microbes use to communicate; and a universal dialect most, if not all, well-socialized bacteria are fluent in called AI-2, which is a molecular mix important for interspecies signaling.

Bassler was one of the first scientist to describe the linguistic skills of the luminous, sea-faring bacterium,Vibrio harveyi, initially discovering two autoinducers the bacteria use to light up−one species-specific and the other universal  (AI-1, a derivative of AHL and the molecular mix, AI-2, respectively).

Then, Bassler and colleagues identified a third Vibrio autoinducer, CAI-1, which, like AI-1, is species-specific.  These three parallel QS circuits synergistically regulate V. harveyi  bioluminescence. All involve the synthesis of autoinducers that bind to and regulate phosphorylation of histidine kinases, says Bassler. The pathways eventually converge to control phosphorylation of a common phospho-relay protein called LuxU, which in turn regulates phosphorylation of LuxO. LuxO ultimately controls the expression of LuxR and that regulates the QS response, she explains.

NO-sensitive QS gene identified in V. harveyi

Building on this information, Boon and collaborators recently found that NO also regulates V. harveyi bioluminescence through the LuxU/LuxO/LuxR pathway and this is modulated by a NO-sensitive H-NOX gene. Like other autoinducers, NO binds to its sensor –in this case, H-NOX, that can transfer phosphate to LuxU.  “Thus NO appears to act as a fourth QS sensing pathway in Vibrio harveyi,” says Boon, who speculates that, in addition to helping Vibrios to judge bacterial density, NO might also enable them to detect the presence of alien cells such as eukaryotes. NO appears important enough to make it a target for the design of novel antibiotics.

However, there is still a lot of fundamental research that needs to be done before we can develop antibiotics based on this pathway,” Boon emphasized at interview. Targeting H-NOX would be tricky, she says, explaining that it would be too toxic to mammals. Boon considers bacteria-specific downstream sites of NO signaling or the proteins involved in QS or c-di-GMP metabolism better bets. “It’s not yet clear whether targeting H-NOX on a ship hull or on evironmental sensors would work,” she advised the reporter, adding that “Nonetheless, a better appreciation of how bacteria control their group behaviors such as QS and biofilm formation is a necessary first step towards intervening in these processes.”

Elizabeth M. Boon, PhD will describe the details of her work at the TB, Toxins and Biofilms symposium on February 9th 2012, co-presented by the Presented by the Chemical Biology Discussion Group and the Emerging Infectious Diseases & Microbiology Discussion Group.

Bonnie Bassler, PhD is scheduled to talk about her latest research at the Discovering Antibacterial and Anticancer Therapeutics in Unexpected Places  symposium on April 4th 2012, presented by the Emerging Infectious Diseases & Microbiology Discussion Group at the New York Academy of Sciences.

Sources:

Boon, E.M., Davis, J.H., Karow, D.S. et al. Characterization of NO binding to prokaryotic homologs of the sGC beta1 H-NOX domain. (2006). Journal of Biological Chemistry. 281: pp. 21892-21902.

Boon, E.M. and Marletta, M.A. Sensitive and selective detection of nitric oxide using an H-NOX domain. (2006). Journal of the American Chemical Society. 128: pp. 10022-10023. Accessed January 20, 2012.

Camilli, A. and Bassler, B.L. Bacterial small-molecule signaling pathways. (2006). Science 311: 1113-1116. Accessed January 20, 2012.

Kelly, R.C., Bolitho, M.E., Higgins, D.A. et al. The Vibrio cholerae quorum-sensing  autoinducer CAI-1 : analysis of the biosynthetic enzyme CqsA. (2009). Nature Chemical Biology. 5 (12) : pp. 891-895. Accessed January 20, 2012.

Liu, N., Taemee, P., Boon, E.M. Characterization of a diguanylate cyclase from Shewanella woodyi with cyclase and phosphodiesterase activities. (2010) Molecular BioSystems : 6, pp.1561-1564. Accessed January 20, 2012.

Taga, M. E. and Bassler, B.L. Chemical communication among bacteria. (2003) Proceedings of the National Academy of Sciences, USA. 100(suppl.2): pp. 14549-14554. Accessed January 20, 2012.

Interviews with Bonnie L. Bassler PhD and Elizabeth M. Boon PhD

Suggested reading:

Bassler, B.L. Small Cells –Big Future. (2010). Molecular Biology of the Cell. 21: pp.3786-3787. Accessed January 20, 2012.

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