Transcriptomic Basis of Serum Resistance and Virulence Related Traits in XDR P. aeruginosa Evolved Under Antibiotic Pressure in a Morbidostat Device

• Main Authors: Mumina Javed, Benedikt Jentzsch, Maximilian Heinrich, Viola Ueltzhoeffer, Silke Peter, Ulrich Schoppmeier, Angel Angelov, Sandra Schwarz, Matthias Willmann
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-01-01
• Series: Frontiers in Microbiology
• Subjects: multi-drug resistance; biofilm formation; evolutionary trajectories; serum susceptibility; colistin; combination drug therapy
• Online Access: https://www.frontiersin.org/articles/10.3389/fmicb.2020.619542/full

Colistin is a last resort antibiotic against the critical status pathogen Pseudomonas aeruginosa. Virulence and related traits such as biofilm formation and serum resistance after exposure to sub-inhibitory levels of colistin have been underexplored. We cultivated P. aeruginosa in a semi-automated morbidostat device with colistin, metronidazole and a combination of the two antibiotics for 21 days, and completed RNA-Seq to uncover the transcriptional changes over time. Strains became resistant to colistin within this time period. Colistin-resistant strains show significantly increased biofilm formation: the cell density in biofilm increases under exposure to colistin, while the addition of metronidazole can remove this effect. After 7 days of colistin exposure, strains develop an ability to grow in serum, suggesting that colistin drives bacterial modifications conferring a protective effect from serum complement factors. Of note, strains exposed to colistin showed a decrease in virulence, when measured using the Galleria mellonella infection model. These phenotypic changes were characterized by a series of differential gene expression changes, particularly those related to LPS modifications, spermidine synthesis (via speH and speE) and the major stress response regulator rpoS. Our results suggest a clinically important bacterial evolution under sub-lethal antibiotic concentration leading to potential for significant changes in the clinical course of infection.