About AMR: Polymicrobial nature of cystic fibrosis infections could influence outcome of antimicrobial therapy

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Several recent papers have investigated how polymicrobial interactions in the cystic fibrosis (CF) lung influence antimicrobial efficacy. These studies demonstrate that microbial metabolites produced by one pathogen can alter the antimicrobial killing of another pathogen, indicating that community composition may need to be considered when choosing the most appropriate antimicrobial strategy for treating CF lung infections.

The lungs of CF patients are chronically colonized with a diverse community of microorganisms that drive frequent pulmonary exacerbations, contributing to the morbidity and mortality of the disease. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most common CF pathogens, and both possess intrinsic and acquired antimicrobial resistance, complicating the treatment of CF infections.

The colonization patterns of S. aureus and P. aeruginosa in the lungs of CF patients are inversely correlated, with S. aureus predominating in pediatric patients and P. aeruginosa predominating in adult patients. Previous studies have suggested that this is driven by the metabolic stress imposed on S. aureus when present in multispecies biofilms with P. aeruginosa. P. aeruginosa produces secondary metabolites, including 2-heptyl-4-hydroxyquinolone-N-oxide (HQNO) and siderophores, which inhibit S. aureus respiration and limit the availability of iron, respectively. Consequently, S. aureus adopts a reduced metabolic state reminiscent of that of small colony variants, a growth phenotype that promotes resistance to aminoglycosides. S. aureus, however, is eventually outcompeted by P. aeruginosa, leading to its cell death (Figure 1A).

 

 

This model is but one scenario of S. aureus and P. aeruginosa interactions in the CF lung, since situations do arise where both pathogens co-colonize the CF lung. Two recent studies highlight how P. aeruginosa S. aureus interactions in co-colonization scenarios might influence antimicrobial efficacy.

In mBio, Orazi and O’Toole consider a scenario in which S. aureus and P. aeruginosa colonize spatially distinct niches in the CF lung, yet interact via diffusible secondary metabolites. They find that HQNO alone increases the survival of S. aureus biofilms upon exposure to vancomycin – the frontline antibiotic for treating methicillin-resistant S. aureus infections. HQNO forces S. aureus to rely on energy from fermentation and arginine catabolism leading to slower growth, which protects S. aureus from vancomycin killing (Figure 1B).

In Antimicrobial Agents and Chemotherapy, Tavernier and colleagues extend the scenario to include an additional CF pathogen, Streptococcus anginosus. Their data support an alternative outcome of antimicrobial efficacy in multispecies biofilm, demonstrating that S. aureus is more susceptible to killing by antibiotics including aminoglycosides and cell wall synthesis inhibitors when grown with P. aeruginosa and S. anginosus. Further, they find that S. aureus secretes metabolites that promote S. anginosus resistance to cell wall synthesis antibiotics, including vancomycin (Figure 1C).

Posing yet another scenario is a study in mBio from Limoli and colleagues, which demonstrates that P. aeruginosa adopts a mucoid phenotype to promote coexistence with S. aureus in the CF lung. In the mucoid state, P. aeruginosa downregulates production of virulence factors, including siderophores and HQNO, thereby reducing the killing of S. aureus – and possibly limiting its effects on the antimicrobial killing of S. aureus (Figure 1D).

These studies highlight how the dynamic nature of polymicrobial communities in the CF airways shape the antimicrobial killing of relevant CF pathogens in unexpected ways. They emphasize the need for models that better mimic the complexity of a pathogen’s environment in order to more precisely measure antimicrobial killing. Such models would not only inform the selection of optimal therapeutic strategies, but could also provide insight into cellular processes that become vulnerable to antimicrobials upon co-culture.

Sources
  1. Filkins LM, Graber JA, Olson DG et al. Co-culture of Staphylococcus aureus with Pseudomonas aeruginosa drives aureus towards fermentative metabolism and reduced viability in a cystic fibrosis model. J. Bacteriol. 197(14), 2252–64 (2015).
  2. Orazi & O’Toole. Pseudomonas aeruginosa alters Staphylococcus aureus sensitivity to vancomycin in a biofilm model of cystic fibrosis infection. mBio. 8(4), e00873–17 (2017).
  3. Tavernier S, Crabbé A, Tuysuz M et al. Community composition determines activity of antibiotics against multispecies biofilms. Agents Chemother. doi:10.1128/AAC.00302-17 (2017).
  4. Limoli DH, Whitfield GB, Kitao T et al., Pseudomonas aeruginosaalginate overproduction promotes coexistence with Staphylococcus aureus in a model of cystic fibrosis respiratory infection.  8( 2) e00186–17 (2017).
About the author

Julie Kaiser is a Ph.D. candidate in Microbiology at the University of Western Ontario in London, Canada. Her research interests range from the impact of microbial communities on human health, to the molecular basis of drug-resistant bacterial infections. Julie enjoys sharing her love for the microbial world through science communication and is the author of Microbiology for Dummies. Follow her on twitter at @jukais.

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