Outbreaks of multidrug-resistant (MDR) Pseudomonas aeruginosa infections within medical institutions have been commonly reported for many years. We now know that many outbreaks are caused by a small group of widely dispersed and MDR P. aeruginosa lineages, which are referred to as “high-risk clones” (HRCs). The best characterized of these HRCs are the MLST genotypes ST235, ST175, and ST111. Unlike typical antibiotic-susceptible P. aeruginosa strains, which are believed to be acquired by patients either directly or indirectly from the natural environment (lakes, streams, soil), HRCs are thought to be acquired from the gastrointestinal (GI) tracts of colonized or infected patients. These HRCs spread from patient to patient within healthcare facilities, where they acquire high levels of antimicrobial resistance due to repeated exposure to antibiotics over long periods of time. What allows HRCs to thrive in the harsh hospital environment while most P. aeruginosa genotypes are restricted to the natural environment? Speculation has focused on two possibilities: (1) HRCs more effectively colonize the GI tract than other P. aeruginosa strains; and (2) HRCs have properties that allow them to better resist eradication by antibiotics. With regard to the latter idea, one obvious explanation is that the ancestors of HRC happened to become MDR, and that this provided a selective advantage in hospital environments awash with antimicrobial agents, allowing these HRCs to persist and spread. However, genomic investigations have revealed that the actual explanation is more complex. Even closely related HRC isolates of the same ST vary markedly in the genetic determinants responsible for their antibiotic resistance, indicating that HRCs were already spreading widely before they became antibiotic resistant. This suggests that specific P. aeruginosa strains became HRCs not because they were antibiotic resistant but because they were genetically adaptable and readily able to become antibiotic resistant. 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 high-risk clones colonize the GI tract better than conventional P. aeruginosa strains. (2) Determine whether high-risk clones have properties that allow them to more readily become resistant to antibiotics. (3) Identify genetic loci that distinguish P. aeruginosa high-risk clones from conventional strains.
|Effective start/end date||5/20/21 → 4/30/23|
- National Institute of Allergy and Infectious Diseases (1R21AI164254-01)
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