Microbial Population Structure Impacts Antibiotic Resistance
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Antibiotic resistance is an urgent and growing concern, and developing novel therapeutic approaches to overcome antibiotic-resistant infections has assumed immense significance. Recently, it has been shown that heterogeneity in a microbial environment can accelerate the development of antibiotic resistance. However, the effect of the spatial distribution of the microbial population itself remains to be investigated. Using the human pathogen Pseudomonas aeruginosa, we show that increasing cell density can drastically impact the survival and growth of antibiotic-resistant mutants in the presence of aminoglycoside antibiotics in a density-dependent manner. Increasing density confers both positive and negative effects to mutant survival, which we term “protection” and “inhibition”, respectively. Using a combination of microbiological assays and biophysical modeling, we find that inhibition is mediated by a low-molecular weight, native by-product of bacterial metabolism that acts in conjunction with aminoglycosides through an effected increase in pH. A wide range of bacterial species are capable of producing inhibition, which is related to their growth by amino acid catabolism. We additionally develop a stochastic model of inhibition in homogeneous environments, which indicates that local density fluctuations on the scale of individual bacteria can significantly alter bacterial survival when colonizing a new environment. This work raises the possibility that the manipulation of population structure and the nutrient environment of microbes in conjunction with the use existing antibiotics could provide novel therapeutic approaches to combat antibiotic resistance.