Rapid Conversion of Pseudomonas aeruginosa to a Spherical Cell Morphotype Facilitates Tolerance to Carbapenems and Penicillins but Increases Susceptibility to Antimicrobial Peptides

Abstract

ABSTRACTThe Gram-negative human pathogenPseudomonas aeruginosatolerates high concentrations of β-lactam antibiotics. Despite inhibiting the growth of the organism, these cell wall-targeting drugs exhibit remarkably little bactericidal activity. However, the mechanisms underlying β-lactam tolerance are currently unclear. Here, we show thatP. aeruginosaundergoes a rapiden massetransition from normal rod-shaped cells to viable cell wall-defective spherical cells when treated with β-lactams from the widely used carbapenem and penicillin classes. When the antibiotic is removed, the entire population of spherical cells quickly converts back to the normal bacillary form. Our results demonstrate that these rapid population-wide cell morphotype transitions function as a strategy to survive antibiotic exposure. Taking advantage of these findings, we have developed a novel approach to efficiently killP. aeruginosaby using carbapenem treatment to induceen massetransition to the spherical cell morphotype and then exploiting the relative fragility and sensitivity of these cells to killing by antimicrobial peptides (AMPs) that are relatively inactive againstP. aeruginosabacillary cells. This approach could broaden the repertoire of antimicrobial compounds used to treatP. aeruginosaand serve as a basis for developing new therapeutic agents to combat bacterial infections.