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Abstract
Chronic coinfections of Staphylococcus aureus and Pseudomonas aeruginosa frequently fail to respond to antibiotic treatment, leading to significant patient morbidity and mortality. Currently, the impact of interspecies interaction on S. aureus antibiotic susceptibility remains poorly understood. In this study, we utilize a panel of P. aeruginosa burn wound and cystic fibrosis (CF) lung isolates to demonstrate that P. aeruginosa alters S. aureus susceptibility to bactericidal antibiotics in a variable, strain-dependent manner and further identify 3 independent interactions responsible for antagonizing or potentiating antibiotic activity against S. aureus. We find that P. aeruginosa LasA endopeptidase potentiates lysis of S. aureus by vancomycin, rhamnolipids facilitate proton-motive force-independent tobramycin uptake, and 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) induces multidrug tolerance in S. aureus through respiratory inhibition and reduction of cellular ATP. We find that the production of each of these factors varies between clinical isolates and corresponds to the capacity of each isolate to alter S. aureus antibiotic susceptibility. Furthermore, we demonstrate that vancomycin treatment of a S. aureus mouse burn infection is potentiated by the presence of a LasA-producing P. aeruginosa population. These findings demonstrate that antibiotic susceptibility is complex and dependent not only upon the genotype of the pathogen being targeted, but also on interactions with other microorganisms in the infection environment. Consideration of these interactions will improve the treatment of polymicrobial infections.
Highlights
S. aureus is responsible for numerous chronic and relapsing infections such as osteomyelitis, endocarditis, and infections of the cystic fibrosis (CF) lung, as well as many penetrating trauma and burn infections, venous leg ulcers, pressure ulcers, and diabetic foot ulcers
We identify the exoproducts responsible for altering S. aureus susceptibility to antibiotic killing, and demonstrate that these compounds are produced at varying levels in P. aeruginosa clinical isolates, with dramatic repercussions for S. aureus antibiotic susceptibility
These findings indicate that the efficacy of antibiotic treatment in polymicrobial infection is determined at the community level, with interspecies interaction playing an important and previously unappreciated role
Summary
S. aureus is responsible for numerous chronic and relapsing infections such as osteomyelitis, endocarditis, and infections of the cystic fibrosis (CF) lung, as well as many penetrating trauma and burn infections, venous leg ulcers, pressure ulcers, and diabetic foot ulcers These infections are notoriously difficult to treat, despite isolates frequently exhibiting full sensitivity to administered antibiotics, as measured in vitro using a Minimum Inhibitory Concentration (MIC) assay. This suggests that environmental factors present in vivo may influence the pathogen’s susceptibility to antibiotic killing While these factors can include physical barriers to antibiotic activity, such as tissue necrosis and low vascularization at a site of infection, or bacterial replication within host phagocytes, treatment failure cannot be fully explained by poor drug penetration [1]. Antibiotic deactivation by resistant organisms within a population can lead to de facto resistance of all members of the community [7,8,9,10]
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