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Antibiotic resistance detection and concomitant species identification of ESKAPE pathogens by proteomics

ABSTRACT: Antimicrobial resistance (AMR) is an increasing challenge for therapy of bacterial infections. Currently, patient treatment is guided by antimicrobial susceptibility testing (AST) using phenotypic assays and species identification by MALDI-ToF biotyping. Bacterial phenotype prediction using omics technologies could offer several advantages over current diagnostic methods. It would allow species identification and AST to be combined in a single measurement, it would eliminate the need for secondary cultivation and could enable the prediction of phenotypes beyond AMR, such as virulence. In this study, the potential of proteomics for clinical microbiology was evaluated in an analysis of 126 clinical isolates covering 16 species including all ESKAPE genera and 30 of the most common AMR determinants. For this purpose, a flexible workflow was developed, which enables to report the AMR phenotype and the species of primary cultures within 2h. Proteomics provided high specificity (99.9%) and sensitivity (94.4 %) for AMR detection, while allowing species identification from very large sequence databases with high accuracy. The results show, that proteomics is well suited for phenotyping clinical bacterial isolates and has the potential to become a valuable diagnostic tool for clinical microbiology in the future.

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ORGANISM(S): Pseudomonas Aeruginosa Pa103 Acinetobacter Baumannii Shigella Sonnei Klebsiella Grimontii Enterococcus Faecium Com15 Klebsiella Pneumoniae Proteus Mirabilis Citrobacter Freundii Complex Escherichia Coli Klebsiella Quasipneumoniae Staphylococcus Aureus Klebsiella Oxytoca Morganella Morganii Subsp. Morganii Enterobacter Cloacae

SUBMITTER: Joerg Doellinger

LAB HEAD: Joerg Doellinger

PROVIDER: PXD056051 | Pride | 2026-03-02

REPOSITORIES: Pride

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Project description:Background: Angiotensin receptorâ€“neprilysin inhibitors (ARNI) have been used in the treatment of heart failure (HF) for several years. Sacubitril/valsartan (Sac/Val) belongs to the group of ARNI and led to a reduction in mortality and pump failure. The mechanisms that mediate the beneficial effects of Sac/Val are not yet fully understood. In this study we investigated whether Sac/Val influences the two proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), in a mouse model of pressure overload-induced HF and in a human cellular model of hypertrophy. Experimental approach: Transverse aortic constriction (TAC) or sham surgery was performed in 8-week old C57BL/6N mice. 14 days after TAC or sham surgery, the animals were randomized into the following 4 groups: 1) sham/vehicle, 2) sham/Sac/Val, 3) TAC/vehicle, and 4) TAC/Sac/Val. Sac/Val (57 mg/kg body weight/day) or vehicle (200 Âµl water) was given for further 6 weeks twice a day. Cardiac function was determined weekly by echocardiography. After 8 weeks, the hearts were taken and further investigated on molecular level. Human induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs) and treated with 100 nM endothelin 1 (ET1) and 40 ÂµM Sac or 13 ÂµM Val or both 40 ÂµM Sac + 13 ÂµM Val while using DMSO as a control. Analyses were performed on transcript and protein level as well as for UPS function. Key results: TAC mice showed a continuous decline in left ventricular function starting from day 14 after surgery. Sac/Val counteracted the deterioration especially of ejection fraction and cardiac output. The HF phenotype was further confirmed by an upregulation of the fetal gene program and of genes associated with fibrosis as well as a downregulation of genes involved in Ca2+ handling in TAC mice and was partially normalized by Sac/Val treatment. Evaluation of the ALP revealed no major impact of TAC or Sac/Val on the expression of ALP key marker. Investigation of the UPS showed a higher chymotrypsin-like activity after TAC, which was normalized by Sac/Val. In hiPSC-CMs, all treatments (Sac, Val, Sac/Val) normalized mean cell area. Sac but not Val prevented ET1-induced hypertrophic gene program and reduced the ET1-induced increase in UPS activity. Gross protein ubiquitination was only lowered in Sac/Val treated cells. The proteomic footprint showed a higher overlap between control, Sac and Sac/Val treated compared to the ET1 and Val groups. Both Sac-containing groups normalized sarcomeric protein levels, while Val mostly changed levels of proteins associated with energy metabolism. Conclusion: Sac/Val improved cardiac function and reduced fibrosis and hypertrophy. Whereas Sac/Val seems to exert its protective role independently of autophagy processes, the data obtained for the UPS suggest that Sac/Val has a beneficial effect on the UPS function. In the hiPSC-CMs, Sac proved to be the component of LCZ696 that mostly prevented the negative effects of ET1 on cell area, gene expression, proteome and UPS function.

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	10-16.quant	Other
	10-16.raw	Raw
	10-16__Report.pdf	Pdf
	1005-14.quant	Other
	1005-14.raw	Raw

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Antibiotic resistance detection and concomitant species identification of ESKAPE pathogens by proteomics

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