P. aeruginosa is an important opportunistic pathogen responsible for a wide range of infections. Antibiotic resistance is fairly common, which hampers effective treatment, especially in chronic infections of CF patients. There is a need to identify new drug targets, which may include primary biosynthetic pathways required for bacterial survival and virulence factor synthesis. The goal of this research is to establish the pathway of fatty acid (Fab) and autoinducer (PAI) biosynthesis and explore their usefulness as novel antimicrobial targets. This linked pathway is an excellent candidate for drug development, because it is responsible for the synthesis of essential cellular components and is also involved in synthesis of conserved central regulatory elements for virulence factor synthesis (quorum sensing). As part of this proposal, an in vitro Fab system will be established using purified recombinant proteins in order to define enzymes leading to synthesis of acyl-acyl carrier protein, which is the substrate for PAI synthesis. Second, in vitro PAI synthesis will be demonstrated using purified PAI synthases, leading to the production of biologically-active PAI. Various Fab and PAI synthesis inhibitors, including thiolactomycin (TLM) and its analogs will be evaluated. The effects of these inhibitors will be studied in vitro and in vivo. The mechanism of TLM resistance will be addressed using clinical isolates of P. aeruginosa, as well as resistant mutants isolated in the laboratory. The successful outcome of this line of investigation should result in the identification of the entire pathway of AI synthesis. These studies should provide a better understanding of the quorum sensing pathways and lead to the identification of novel anti microbial targets and antimicrobials effective against gram-negative pathogens.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Chin, Jean
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Colorado State University-Fort Collins
Schools of Veterinary Medicine
Fort Collins
United States
Zip Code
Mistry, Anita; Warren, Mark S; Cusick, John K et al. (2013) High-level pacidamycin resistance in Pseudomonas aeruginosa is mediated by an opp oligopeptide permease encoded by the opp-fabI operon. Antimicrob Agents Chemother 57:5565-71
Walker, Travis S; Bais, Harsh Pal; Deziel, Eric et al. (2004) Pseudomonas aeruginosa-plant root interactions. Pathogenicity, biofilm formation, and root exudation. Plant Physiol 134:320-31
Barekzi, Nazir; Joshi, Swati; Irwin, Scott et al. (2004) Genetic characterization of pcpS, encoding the multifunctional phosphopantetheinyl transferase of Pseudomonas aeruginosa. Microbiology 150:795-803
Chuanchuen, Rungtip; Karkhoff-Schweizer, RoxAnn R; Schweizer, Herbert P (2003) High-level triclosan resistance in Pseudomonas aeruginosa is solely a result of efflux. Am J Infect Control 31:124-7
Schweizer, Herbert P (2003) Efflux as a mechanism of resistance to antimicrobials in Pseudomonas aeruginosa and related bacteria: unanswered questions. Genet Mol Res 2:48-62
Hoang, Tung T; Sullivan, Sarah A; Cusick, John K et al. (2002) Beta-ketoacyl acyl carrier protein reductase (FabG) activity of the fatty acid biosynthetic pathway is a determining factor of 3-oxo-homoserine lactone acyl chain lengths. Microbiology 148:3849-56
Chuanchuen, Rungtip; Narasaki, Craig T; Schweizer, Herbert P (2002) The MexJK efflux pump of Pseudomonas aeruginosa requires OprM for antibiotic efflux but not for efflux of triclosan. J Bacteriol 184:5036-44
Chuanchuen, R; Beinlich, K; Hoang, T T et al. (2001) Cross-resistance between triclosan and antibiotics in Pseudomonas aeruginosa is mediated by multidrug efflux pumps: exposure of a susceptible mutant strain to triclosan selects nfxB mutants overexpressing MexCD-OprJ. Antimicrob Agents Chemother 45:428-32
Schweizer, H P; Hoang, T T; Propst, K L et al. (2001) Vector design and development of host systems for Pseudomonas. Genet Eng (N Y) 23:69-81
Schweizer, H P; Chuanchuen, R (2001) Small broad-host-range lacZ operon fusion vector with low background activity. Biotechniques 31:1258, 1260, 1262

Showing the most recent 10 out of 17 publications