Induced Heteroresistance in Carbapenem-Resistant Acinetobacter baumannii (CRAB) via Exposure to Human Pleural Fluid (HPF) and Its Impact on Cefiderocol Susceptibility

Vista sencilla de ítem
dc.citation.titleInternational Journal of Molecular Sciences
dc.citation.volume24
dc.contributor.orcidhttps://orcid.org/0000-0003-1896-8450
dc.contributor.orcidhttps://orcid.org/0000-0002-4780-5311
dc.contributor.orcidhttps://orcid.org/0000-0001-5840-5869
dc.contributor.orcidhttps://orcid.org/0000-0001-9644-9088
dc.contributor.orcidhttps://orcid.org/0000-0002-6298-7811
dc.contributor.orcidhttps://orcid.org/0000-0002-9904-7890
dc.creatorMezcord, Vyanka
dc.creatorEscalante, Jenny
dc.creatorNishimura, Brent
dc.creatorTraglia, German M.
dc.creatorSharma, Rajnikant
dc.creatorVallé, Quentin
dc.creatorTuttobene, Marisel Romina
dc.creatorSubils, Tomás
dc.creatorMarin, Ingrid
dc.creatorPasteran, Fernando
dc.creatorActis, Luis A.
dc.creatorTolmasky, Marcelo E.
dc.creatorBonomo, Robert A.
dc.creatorRao, Gauri
dc.creatorRamírez, María Soledad
dc.date.accessioned2024-04-11T14:53:56Z
dc.date.available2024-04-11T14:53:56Z
dc.date.issued2023-07-21
dc.description.abstractInfections caused by Carbapenem-resistant Acinetobacter baumannii (CRAB) isolates, such as hospital-acquired pneumonia (HAP), bacteremia, and skin and soft tissue infections, among others, are particularly challenging to treat. Cefiderocol, a chlorocatechol-substituted siderophore antibiotic, was approved by the U.S. Food and Drug Administration (FDA) in 2019 and prescribed for the treatment of CRAB infections. Despite the initial positive treatment outcomes with this antimicrobial, recent studies reported a higher-than-average all-cause mortality rate in patients treated with cefiderocol compared to the best available therapy. The cause(s) behind these outcomes remains unconfirmed. A plausible hypothesis is heteroresistance, a phenotype characterized by the survival of a small proportion of cells in a population that is seemingly isogenic. Recent results have demonstrated that the addition of human fluids to CRAB cultures leads to cefiderocol heteroresistance. Here, we describe the molecular and phenotypic analyses of CRAB heteroresistant bacterial subpopulations to better understand the nature of the less-than-expected successful outcomes after cefiderocol treatment. Isolation of heteroresistant variants of the CRAB strain AMA40 was carried out in cultures supplemented with cefiderocol and human pleural fluid (HPF). Two AMA40 variants, AMA40 IHC1 and IHC2, were resistant to cefiderocol. To identify mutations and gene expression changes associated with cefiderocol heteroresistance, we subjected these variants to whole genome sequencing and global transcriptional analysis. We then assessed the impact of these mutations on the pharmacodynamic activity of cefiderocol via susceptibility testing, EDTA and boronic acid inhibition analysis, biofilm formation, and static time-kill assays. Heteroresistant variants AMA40 IHC1 and AMA40 IHC2 have 53 chromosomal mutations, of which 40 are common to both strains. None of the mutations occurred in genes associated with high affinity iron-uptake systems or β-lactam resistance. However, transcriptional analyses demonstrated significant modifications in levels of expression of genes associated with iron-uptake systems or β-lactam resistance. The blaNDM-1 and blaADC-2, as well as various iron-uptake system genes, were expressed at higher levels than the parental strain. On the other hand, the carO and ompA genes’ expression was reduced. One of the mutations common to both heteroresistant strains was mapped within ppiA, a gene associated with iron homeostasis in other species. Static time-kill assays demonstrated that supplementing cation-adjusted Mueller–Hinton broth with human serum albumin (HAS), the main protein component of HPF, considerably reduced cefiderocol killing activity for all three strains tested. Notably, collateral resistance to amikacin was observed in both variants. We conclude that exposing CRAB to fluids with high HSA concentrations facilitates the rise of heteroresistance associated with point mutations and transcriptional upregulation of genes coding for β-lactamases and biofilm formation. The findings from this study hold significant implications for understanding the emergence of CRAB resistance mechanisms against cefiderocol treatment. This understanding is vital for the development of treatment guidelines that can effectively address the challenges posed by CRAB infections.
dc.description.filFil: Mezcord, Vyanka. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science. Center for Applied Biotechnology Studies; United States.
dc.description.filFil: Escalante, Jenny. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science. Center for Applied Biotechnology Studies; United States.
dc.description.filFil: Nishimura, Brent. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science. Center for Applied Biotechnology Studies; United States.
dc.description.filFil: Traglia, German M. Universidad de la República. CENUR Litoral Norte. Departamento de Ciencias Biológicas. Unidad de Genómica y Bioinformática; Uruguay.
dc.description.filFil: Sharma, Rajnikant. University of North Carolina. UNC Eshelman School of Pharmacy; United States.
dc.description.filFil: Vallé, Quentin. University of North Carolina. UNC Eshelman School of Pharmacy; United States.
dc.description.filFil: Tuttobene, Marisel Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Biología Molecular; Argentina.
dc.description.filFil: Tuttobene, Marisel Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Subils, Tomás. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Procesos Biotecnológicos y Químicos de Rosario (IPROBYQ-CONICET); Argentina.
dc.description.filFil: Marin, Ingrid. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science. Center for Applied Biotechnology Studies; United States.
dc.description.filFil: Pasteran, Fernando. ANLIS "Dr. Carlos G. Malbrán". Instituto Nacional de Enfermedades Infecciosas. Servicio Antimicrobianos. National Regional Reference Laboratory for Antimicrobial Resistance (NRL); Argentina.
dc.description.filFil: Actis, Luis A. Miami University. Department of Microbiology; United States.
dc.description.filFil: Tolmasky, Marcelo E. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science; United States.
dc.description.filFil: Bonomo, Robert A. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Research Service and GRECC; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics; United States.
dc.description.filFil: Bonomo, Robert A. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Rao, Gauri. University of North Carolina. UNC Eshelman School of Pharmacy; United States.
dc.description.filFil: Ramírez, María Soledad. California State University Fullerton. College of Natural Sciences and Mathematics. Center for Applied Biotechnology Studies. Department of Biological Science. Center for Applied Biotechnology Studies; United States.
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
dc.description.sponsorshipProject RAISE, U.S. Department of Education HSI-STEM: award number P031C160152
dc.description.sponsorshipNational Institute on Minority Health and Health Disparities, National Institute of Health (NIH): grant MHRT 2T37MD001368
dc.description.sponsorshipGeriatric Research Education and Clinical Center VISN 10
dc.description.sponsorshipBiomedical Laboratory Research & Development Service of the VA Office of Research and Development: award number 1I01BX001974
dc.description.sponsorshipNational Institutes of Health (NIH): SC3GM125556, R01AI100560, R01AI063517, R01AI072219, 2R15 AI047115
dc.description.sponsorshipCleveland Department of Veterans Affairs
dc.description.versionpeerreviewed
dc.format.extent1-16
dc.identifier.issn1422-0067
dc.identifier.urihttps://hdl.handle.net/2133/26868
dc.language.isoen
dc.publisherMDPI
dc.relation.publisherversionhttps://doi.org/10.3390/ijms241411752
dc.relation.publisherversionhttps://www.mdpi.com/1422-0067/24/14/11752
dc.rightsopenAccess
dc.rights.holderMezcord, Vyanka
dc.rights.holderEscalante, Jenny
dc.rights.holderNishimura, Brent
dc.rights.holderTraglia, German M.
dc.rights.holderSharma, Rajnikant
dc.rights.holderVallé, Quentin
dc.rights.holderTuttobene, Marisel Romina
dc.rights.holderSubils, Tomás
dc.rights.holderMarin, Ingrid
dc.rights.holderPasteran, Fernando
dc.rights.holderActis, Luis A.
dc.rights.holderTolmasky, Marcelo E.
dc.rights.holderBonomo, Robert A.
dc.rights.holderRao, Gauri
dc.rights.holderRamírez, María Soledad
dc.rights.holderUniversidad Nacional de Rosario
dc.rights.textAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAcinetobacter baumannii
dc.subjectHuman pleural fluid
dc.subjectCefiderocol
dc.subjectNDM-1
dc.subjectCarbapenem-resistance
dc.subjectWhole-genome sequencing
dc.subjectAntibiotic susceptibility assays
dc.subjectStatic killing-assay
dc.titleInduced Heteroresistance in Carbapenem-Resistant Acinetobacter baumannii (CRAB) via Exposure to Human Pleural Fluid (HPF) and Its Impact on Cefiderocol Susceptibility
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

Archivos

Bloque original
Mostrando 1 - 1 de 1
Miniatura
Nombre:
ijms-24-11752.pdf
Tamaño:
1.33 MB
Formato:
Adobe Portable Document Format
Descargar
Bloque de licencias
Mostrando 1 - 1 de 1
Nombre:
license.txt
Tamaño:
3.87 KB
Formato:
Item-specific license agreed upon to submission
Descripción:
Descargar

Colecciones

(FBIOyF) Departamento de Bioquímica Clínica - Artículos