Disruption of cross-feeding inhibits pathogen growth in cystic fibrosis sputum

A critical limitation in the management of cystic fibrosis (CF) lung infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient response to therapy. Underlying this disconnect is the inability to accurately recapitulate the in vivo airway environment and complex polymicrobial communities in vitro. We posit that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on co-colonizing organisms for nutrients (i.e. cross-feeding), we hypothesized that multi-drug resistant P. aeruginosa may be indirectly targeted by inhibiting growth of its metabolic partners. To test our hypothesis, we collected sputum from adult CF subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed variable susceptibility to multiple antibiotics when grown in monoculture. However, when P. aeruginosa was cultured under co-operative conditions in which they were dependent on anaerobic, mucin-degrading bacteria for nutrients, both pathogen and anaerobic growth was constrained despite their intrinsic antibiotic resistance. These data suggest that control of chronic polymicrobial infections may be achieved by exploiting obligate or facultative relationships among bacterial community members.