High-Risk Clones of Pseudomonas aeruginosa

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Project Summary Outbreaks of multidrug-resistant (MDR) Pseudomonas aeruginosa infections within medical institutions have been commonly reported for many years. We now know that most of these outbreaks are caused by a small group of widely dispersed MDR P. aeruginosa lineages, which are have been referred to as “high-risk clones” (HRCs). HRCs are highly antibiotic resistant PA lineages that have spread across countries and even continents to cause large numbers of infections. They emerged in the 1980s and 1990s and then rapidly disseminated. The best characterized HRCs are the multilocus sequence types (MLSTs) ST235, ST175, and ST111. HRCs are problematic for two reasons: (1) Because they readily spread within and between hospitals, they cause a disproportionate number of infections. (2) They are highly resistant to antibiotics. In fact, it appears that most MDR PA strains worldwide belong to these few HRC lineages. As expected, HRCs have also been linked to particularly poor outcomes. What has allowed HRCs to spread so widely and to become so resistant to antibiotics while the vast majority of P. aeruginosa STs are cultured only once and are antibiotic susceptible? Relatively few experiments have been performed to address this important question, but speculation has focused on two possibilities: (1) HRCs more effectively colonize the gastrointestinal (GI) tract than other P. aeruginosa strains. The GI tracts of patients are a major reservoir for P. aeruginosa in the hospital setting, and strains of P. aeruginosa capable of more effectively colonizing this niche would have a considerable advantage in persisting and spreading to new patients within and between institutions. (2) HRCs have properties that allow them to more efficiently acquire antibiotic resistance genes and alleles than conventional P. aeruginosa strains. Populations of HRCs harbor an impressive array of mobile genetic elements and chromosomal alleles that encode antibiotic resistance, suggesting that they are more amendable to acquiring exogenous DNA and evolving mutations than conventional strains. We hypothesize that HRCs are better able to colonize the GI tract and better able to acquire antibiotic-resistance determinants than conventional P. aeruginosa strains. To test these hypotheses, we will perform the following Specific Aims: (1) Use a mouse model to determine whether HRCs colonize the GI tract better than conventional P. aeruginosa strains. (2) Determine whether HRCs have properties that allow them to more readily become resistant to antibiotics. (3) Identify genetic loci that distinguish HRCs from conventional strains. Completion of these aims will provide insights into the mechanisms by which HRCs persist in the hospital environment and acquire MDR phenotypes. These insights in turn will highlight vulnerabilities that can be targeted by therapeutic interventions that prevent the spread and limit the antibiotic resistance of HRCs. Such interventions would impact not only some of the most common P. aeruginosa infections but also those that are the most difficult to treat.