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Entropically driven aggregation of bacteria by host polymers promotes antibiotic tolerance in Pseudomonas aeruginosa

Patrick R. Secor,L. Michaels,A. Ratjen,Laura K. Jennings,Pradeep K. Singh

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Bacteria live in aggregates at sites of chronic infection, and aggregated growth is thought to be important in producing key infection phenotypes such as antibiotic tolerance. We found that entropic forces generated by polymers abundant at chronic infection sites can cause bacteria to aggregate by a mechanism known as “depletion aggregation.” This aggregation mechanism does not require biofilm formation functions, but it does cause bacteria to become much less susceptible to killing by antibiotics. These findings indicate that aggregation could be a default growth mode at infection sites. It might be useful to target mechanisms of depletion-mediated antibiotic tolerance for the treatment of chronic infections. Bacteria causing chronic infections are generally observed living in cell aggregates suspended in polymer-rich host secretions, and bacterial phenotypes induced by aggregated growth may be key factors in chronic infection pathogenesis. Bacterial aggregation is commonly thought of as a consequence of biofilm formation; however the mechanisms producing aggregation in vivo remain unclear. Here we show that polymers that are abundant at chronic infection sites cause bacteria to aggregate by the depletion aggregation mechanism, which does not require biofilm formation functions. Depletion aggregation is mediated by entropic forces between uncharged or like-charged polymers and particles (e.g., bacteria). Our experiments also indicate that depletion aggregation of bacteria induces marked antibiotic tolerance that was dependent on the SOS response, a stress response activated by genotoxic stress. These findings raise the possibility that targeting conditions that promote depletion aggregation or mechanisms of depletion-mediated tolerance could lead to new therapeutic approaches to combat chronic bacterial infections.

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