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Abstract
Cefiderocol (CFDC) is a novel chlorocatechol-substituted siderophore antibiotic approved to treat complicated urinary tract infections (cUTI) and hospital-acquired and ventilator-acquired pneumonia (HAP/VAP). Previous work determined that albumin-rich human fluids increase the minimum inhibitory concentration (MICs) of Acinetobacter baumannii against CFDC and reduce the expression of genes related to iron uptake systems. This latter effect may contribute to the need for higher concentrations of CFDC to inhibit growth. The presence of human urine (HU), which contains low albumin concentrations, did not modify MIC values of two carbapenem-resistant A. baumannii. Levels of resistance to CFDC were not modified by HU in strain AMA40 but were reduced in strain AB5075. Expanding the studies to other carbapenem-resistant A. baumannii isolates showed that the presence of HU resulted in unmodified or reduced MIC of CDFC values. The expression of piuA, pirA, bauA, and bfnH determined by qRT-PCR was enhanced in A. baumannii AMA40 and AB5075 by the presence of HU in the culture medium. All four tested genes code for functions related to recognition and transport of ferric-siderophore complexes. The effect of HU on expression of pbp1, pbp3, blaOXA-51-like, blaADC, and blaNDM-1, genes associated with resistance to β-lactams, as well as genes coding for efflux pumps and porins was variable, showing dependence with the strain analyzed. We conclude that the lack of significant concentrations of albumin and free iron in HU makes this fluid behave differently from others we tested. Unlike other albumin rich fluids, the presence of HU does not impact the antibacterial activity of CFDC when tested against A. baumannii.
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1 California State University Fullerton, Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, Fullerton, USA (GRID:grid.253559.d) (ISNI:0000 0001 2292 8158)
2 Universidad Nacional de Rosario, Área Biología Molecular, Facultad de Ciencias Bioquímicas y Farmacéuticas, Rosario, Argentina (GRID:grid.10814.3c) (ISNI:0000 0001 2097 3211); Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Argentina (GRID:grid.501777.3) (ISNI:0000 0004 0638 1836)
3 Instituto de Procesos Biotecnológicos y Químicos de Rosario (IPROBYQ, CONICET-UNR), Rosario, Argentina (GRID:grid.501777.3)
4 ANLIS Dr. Carlos G. Malbrán, National Regional Reference Laboratory for Antimicrobial Resistance (NRL), Servicio Antimicrobianos, Instituto Nacional de Enfermedades Infecciosas, Buenos Aires, Argentina (GRID:grid.419202.c) (ISNI:0000 0004 0433 8498)
5 CONICET, Centro de Referencia Para Lactobacilos (CERELA), Tucumán, Argentina (GRID:grid.423606.5) (ISNI:0000 0001 1945 2152)
6 Instituto Leloir–IIBBA CONICET, Buenos Aires, Argentina (GRID:grid.423606.5) (ISNI:0000 0001 1945 2152)
7 Miami University, Department of Microbiology, Oxford, USA (GRID:grid.259956.4) (ISNI:0000 0001 2195 6763)
8 Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Research Service and GRECC, Cleveland, USA (GRID:grid.410349.b) (ISNI:0000 0004 5912 6484); Case Western Reserve University School of Medicine, Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847); CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847)