New research from the University of North Carolina at Chapel Hill shows that different strains of Pseudomonas aeruginosa can affect the susceptibility of Staphylococcus aureus to a range of different antibiotics. Depending on the antibiotic and the strain, Ps. aeruginosa can either enhance killing or provide protection against the antibiotics tested. Given the high treatment failures, especially in chronic infections such as cystic fibrosis where Ps. aeruginosa and S. aureus can be found together, this work highlights the importance of understanding microbial interactions when administering antibiotics.

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.

Author summary

Accurate prediction of antimicrobial efficacy is essential for successful treatment of a bacterial infection. While many studies have considered the impacts of genetically encoded mechanisms of resistance, nongenetic determinants of antibiotic susceptibility during infection remain poorly understood. Here we show that a single interspecies interaction between 2 human pathogens, S. aureus and P. aeruginosa, can completely transform the antibiotic susceptibility profile of S. aureus. Through multiple distinct mechanisms, P. aeruginosa can antagonize or potentiate the efficacy of multiple classes of antibiotics against S. aureus. We identify the exoproducts responsible for altering S. aureus susceptibility to antibiotic killing, and furthermore demonstrate that these compounds are produced at varying levels in P. aeruginosa clinical isolates, with dramatic repercussions for S. aureus antibiotic susceptibility. Finally, we use a mouse model of P. aeruginosa–S. aureus coinfection to demonstrate that the presence of P. aeruginosasignificantly alters the outcome of S. aureus antibiotic therapy in a host. 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.

Reference

Pseudomonas aeruginosa exoproducts determine antibiotic efficacy against Staphylococcus aureus  Radlinski L, Rowe SE, Kartchner LB, Maile R, Cairns BA, et al. (2017) Pseudomonas aeruginosa exoproducts determine antibiotic efficacy against Staphylococcus aureus. PLOS Biology 15(11): e2003981. https://doi.org/10.1371/journal.pbio.2003981