Antibiotic cross-protection enables resistant bacteria to protect other bacteria that would be otherwise susceptible to the drug. Cefiderocol is the first siderophore cephalosporin antibiotic approved for treating Gram-negative bacterial infections, including carbapenem-resistant Pseudomonas aeruginosa strains. While highly effective, CFDC resistance has been detected clinically, and mechanisms of resistance and cross-protection are not completely understood. In this study, we used experimental evolution and whole genome sequencing to identify cefiderocol resistance mechanisms and evaluated the trade-offs of evolving resistance. We found some cefiderocol-resistant populations evolved cross-protective social behavior, preventing cefiderocol killing of susceptible siblings. Notably, cross-protection was driven by increased secretion of bacterial iron-binding siderophores, which is unique from previously described antibiotic degradation mediated cross-protection. While concerning, we also showed that resistance can be selected against in drug-free environments. Deciphering the costs associated with antibiotic resistance might aid the development of evolution-informed therapeutic approaches to delay the evolution of antibiotic resistance.
During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased siderophore gene expression, causing macrophage ferroptosis and lysis. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.
During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.
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