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

• Published in: Frontiers in microbiology Vol. 11; p. 619542
• Main Authors: Javed, Mumina, Jentzsch, Benedikt, Heinrich, Maximilian, Ueltzhoeffer, Viola, Peter, Silke, Schoppmeier, Ulrich, Angelov, Angel, Schwarz, Sandra, Willmann, Matthias
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 25-01-2021
• Subjects: biofilm formation; colistin; combination drug therapy; evolutionary trajectories; Microbiology; multi-drug resistance; serum susceptibility; multi-drug resistance; combination drug therapy; automated devices; serum susceptibility; bacterial fitness; biofilm formation; evolutionary trajectories; colistin
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2020.619542

Colistin is a last resort antibiotic against the critical status pathogen
. Virulence and related traits such as biofilm formation and serum resistance after exposure to sub-inhibitory levels of colistin have been underexplored. We cultivated
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
infection model. These phenotypic changes were characterized by a series of differential gene expression changes, particularly those related to LPS modifications, spermidine synthesis (
and
) and the major stress response regulator
. 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.