title: Effect of multidrug resistance-conferring mutations on the fitness and virulence of Pseudomonas aeruginosa.
abstract: BACKGROUND
  Multidrug resistance has become a quandary in the treatment of bacterial infections. The effect of resistance mutations and the fitness cost on the pathogenicity of Pseudomonas aeruginosa is not well established. The objective of this study was to examine the impact of multidrug resistance on the fitness and virulence of P. aeruginosa.
  
  
  METHODS
  Fourteen P. aeruginosa strains with various resistance mechanisms were used. In vitro growth of these isolates was investigated in full-strength and 0.25-strength Mueller-Hinton broth (MHB). Exponential growth rates were estimated from serial bacterial burden over 24 h. In vitro growth of two multidrug-resistant strains (PAO1ΔmexRΔoprD and PA9019) was studied when each was grown in co-culture with wild-type strain PAO1. In vivo growth was compared between PAO1 and PAO1ΔmexRΔopD using a murine pneumonia model; virulence over 10 days was studied in six isolates.
  
  
  RESULTS
  Significant reduction in growth rate was observed in selected mutants (P < 0.01). PAO1 out-competed PAO1ΔmexRΔoprD and PA9019 in vitro, and in vivo growth of PAO1 was faster than PAO1ΔmexRΔoprD. Compared with PAO1, PAO1ΔmexR and PAO1ΔoprD showed a slight reduction in mortality rate; significantly lower mortality was seen in PAO1ΔmexRΔoprD (P < 0.01). However, virulence of PA9019 was not significantly different from that of PAO1.
  
  
  CONCLUSIONS
  Specific resistance mutations were associated with fitness cost in P. aeruginosa, and accumulation of such mutations was associated with a reduction in virulence. However, it was difficult to predict the impact in clinical isolates. Knowledge of multidrug resistance mechanisms and compensatory mutations would likely be helpful.
authors.affiliation: University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Kamilia
authors.initials: K
authors.lastname: Abdelraouf
authors.forename: Samer
authors.initials: S
authors.lastname: Kabbara
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Ledesma
authors.forename: Keith
authors.initials: K
authors.lastname: Poole
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
mesh_terms: D000818:Animals; D058491:Bacterial Load; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D051379:Mice; D009154:Mutation; D018410:Pneumonia, Bacterial / Q000382:microbiology; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity* / Q000502:physiology*; D012376:Rodent Diseases / Q000382:microbiology; D014774:Virulence
chemical_list: D003470:Culture Media