BlaGES-6 producing Pseudomonas aeruginosa ST235 is involved in resistance to different β-lactams
Telma de Sousa1, Sandro Machado2, Márcia Carvalho3
1MicroART-Antibiotic Resistance Team, Department of Veterinary Sciences, University of Trás-os Montes and Alto Douro, 5000-801, Vila Real, Portugal; Department of Genetics and Biotechnology, University of Trás-os-Montes and Alto Douro, 5000-801, Vila Real, Portugal; Functional Genomics and Proteomics Unit, University of Trás-os-Montes and Alto Douro, 5000-801, Vila Real, Portugal; Associated Laboratory for Green Chemistry, University NOVA of Lisbon, 1099-085, Caparica, Portugal.
Abstract:
Multidrug resistance in Pseudomonas aeruginosa, particularly resistance to carbapenem, represents a major challenge for public health. This study investigated resistance mechanisms in three P. aeruginosa isolates: HU63 (blaGES-6 carbapenemase-positive), HU141 (carbapenem-resistant without carbapenemase), and PAO1 (control). Genomic analysis revealed distinct sequence types (ST235 for HU63, ST253 for HU141) and chromosomal integration of resistance genes. HU63 harbored diverse resistance mechanisms, including β-lactamases (blaGES-6, blaPDC-35, blaOXA-488) and efflux pumps. Minimum inhibitory concentration assays demonstrated HU63's resistance to all β-lactams tested (meropenem, imipenem-cilastatin, ceftazidime, piperacillin-tazobactam), while HU141 remained susceptible except to cefoxitin and cloxacillin. Time-kill assays revealed tolerance phenotypes, with HU63 showing regrowth after 8-24 h despite initial reductions in bacterial density. Gene expression varied significantlydepending on the antibiotic and the isolate. The HU63 isolate (GES-6 positive) stands out for its marked induction of blaGES-6 in all the antibiotics tested, contributing to its resistance to carbapenems and broad-spectrum cephalosporins. These expression profiles corroborate the classic molecular mechanisms of resistance: regulation of entry pores (oprD), activation of efflux pumps (mexA) and production of β-lactamases (blaGES-6, ampC) adapted to each situation. These findings underscore the multifactorial nature of resistance in Carbapenem-resistant Pseudomonas aeruginosa (CRPA), combining enzymatic inactivation, efflux, and genetic adaptability. The study emphasizes the urgent need for genomic surveillance to track high-risk clones and develop therapies targeting tolerance mechanisms alongside traditional resistance.
Insights
Multidrug resistance in Pseudomonas aeruginosa, especially to carbapenems, is a public health threat. This study reveals complex resistance mechanisms, including specific gene induction and adaptability, highlighting the need for genomic surveillance and novel therapies.
Area of Science:
- Microbiology
- Genomics
- Infectious Diseases
- Antimicrobial Resistance
Background:
- Multidrug resistance (MDR) in Pseudomonas aeruginosa, particularly carbapenem resistance (CRPA), poses a significant global health challenge.
- Understanding the diverse resistance mechanisms employed by P. aeruginosa is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate and compare the resistance mechanisms of different P. aeruginosa isolates, including carbapenemase-positive and carbapenem-resistant strains.
- To analyze the genomic basis, gene expression, and phenotypic resistance profiles associated with multidrug resistance in P. aeruginosa.
Main Methods:
- Genomic analysis to identify sequence types and resistance genes.
- Minimum Inhibitory Concentration (MIC) and time-kill assays to determine antibiotic susceptibility and bacterial killing kinetics.
- Gene expression analysis to quantify the induction of key resistance genes (e.g., blaGES-6, mexA, oprD) under antibiotic pressure.
Main Results:
- Genomic analysis identified distinct sequence types and chromosomal integration of resistance genes in the P. aeruginosa isolates.
- The blaGES-6 positive isolate (HU63) exhibited resistance to all tested β-lactams, driven by significant blaGES-6 induction and other resistance mechanisms.
- Time-kill assays revealed tolerance phenotypes, with regrowth observed despite initial bacterial density reduction, indicating complex resistance strategies.
Conclusions:
- Carbapenem resistance in P. aeruginosa is multifactorial, involving enzymatic inactivation (β-lactamases), efflux pumps, and genetic adaptability.
- The marked induction of blaGES-6 in response to antibiotics is a key factor in carbapenem and broad-spectrum cephalosporin resistance.
- Genomic surveillance and targeting tolerance mechanisms are essential for combating high-risk CRPA clones and improving therapeutic outcomes.
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