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

Abstract

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.

Maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 9: Polymyxins: colistin

“…This may help to explain the observed diversification of P. aeruginosa in natural cystic fibrosis lung infections (Wright et al., 2013 ). Exposition of a P. aeruginosa clinical strain to sub‐inhibitory concentrations of colistin (2 μg/mL) increased biofilm formation, loss in susceptibility to serum and a decrease in virulence determined with Galleria mellonella model of infection (Javed et al., 2021 ). …”

“…Exposition of a P. aeruginosa clinical strain to sub‐inhibitory concentrations of colistin (2 μg/mL) increased biofilm formation, loss in susceptibility to serum and a decrease in virulence determined with Galleria mellonella model of infection (Javed et al., 2021 ).…”

Top-Down Genomic Surveillance Approach To Investigate the Genomic Epidemiology and Antibiotic Resistance Patterns of Enterococcus faecium Detected in Cancer Patients in Arkansas

“…Daptomycin (DAP) is a cyclic lipopeptide antibiotic that has become the cornerstone in the therapeutic treatment for severe infections caused by VREfm and methicillin-resistant Staphylococcus aureus (MRSA) infections ( 13 – 15 ). As a last resort antibiotic, DAP is used in combination with other drugs or in sequential regimens after the failure of standard treatments ( 16 ) such as vancomycin (VAN) for infections caused by VREfm ( 17 ). Although DAP resistance in E. faecium is still rare, there has been an increase in recent years of treatment failures related to an emergence of DAP-nonsusceptible strains ( 18 , 19 ).…”

Top-Down Genomic Surveillance Approach to Investigate the Genomic Epidemiology and Antibiotic Resistance Patterns ofEnterococcus faeciumDetected in Cancer Patients in Arkansas

“…Daptomycin (DAP) is a cyclic lipopeptide antibiotic that has become the cornerstone in the therapeutic treatment for severe infections caused by VREfm and methicillin-resistant S. aureus (MRSA) infections (13)(14)(15). As a last resort antibiotic, DAP is used in combination with other drugs or in sequential regimens after the failure of standard treatments (16) such as vancomycin (VAN) for infections caused by VREfm (17). Although DAP resistance in E. faecium is still rare, there has been an increase in recent years of treatment failures related to an emergence of DAP non-susceptible strains (18,19).…”