Human Serum Proteins and Susceptibility of Acinetobacter baumannii to Cefiderocol: Role of Iron Transport

Abstract

Cefiderocol, a recently introduced antibiotic, has a chemical structure that includes a cephalosporin that targets cell wall synthesis and a chlorocatechol siderophore moiety that facilitates cell penetration by active iron transporters. Analysis of the effect that human serum, human serum albumin, and human pleural fluid had on growing Acinetobacter baumannii showed that genes related to iron uptake were down-regulated. At the same time, β-lactamase genes were expressed at higher levels. The minimum inhibitory concentrations of this antimicrobial in A. baumannii cells growing in the presence of human serum, human serum albumin, or human pleural fluid were higher than those measured when these fluids were absent from the culture medium. These results correlate with increased expression levels of β-lactamase genes and the down-regulation of iron uptake-related genes in cultures containing human serum, human serum albumin, or human pleural fluid. These modifications in gene expression could explain the less-than-ideal clinical response observed in patients with pulmonary or bloodstream A. baumannii infections. The exposure of the infecting cells to the host’s fluids could cause reduced cefiderocol transport capabilities and increased resistance to β-lactams. The regulation of genes that could impact the A. baumannii susceptibility to cefiderocol, or other antibacterials, is an understudied phenomenon that merits further investigation.

Cefiderocol: Systematic Review of Mechanisms of Resistance, Heteroresistance and In Vivo Emergence of Resistance

“…Finally, it has recently been suggested that in vitro susceptibility testing of cefiderocol against A. baumannii may overestimate its activity compared with conditions in vivo [ 76 ]. Specifically, cefiderocol MIC was 2- to 16-fold higher in the presence of human serum, human serum albumin, or human pleural fluid in the culture medium [ 76 ].…”

Acinetobacter baumannii response to cefiderocol challenge in human urine

“…The model strains AB0057 and AYE were included among the tested strains. A previously observed increase in the AB0057 MIC to CDFC when this isolate was cultured in presence of HPF was noted 17 . However, in this case, changes in MIC were not observed under HU conditions (Fig.…”

“…1 A,B). Previous results showed that when the AB5075, AMA16 and AB0057 CRAB strains were exposed to pure 3.5% HSA, or 4% HPF or 100% HS, fluids containing HSA, the transcriptional expression levels of these genes were down regulated for most of the conditions and strains studied 17 . The total Fe concentration was determined in 3.5% HSA and HU, achieving 72 µM; no additional iron was detected, respectively (as determined by a colorimetric iron assay kit, Sigma-Aldrich, MO, USA).…”

“…The presence of these fluids creates a hostile environment by limiting nutrients, such as iron, or actively damaging the bacterial cells through immunity mechanisms 9 , 10 . For example, when A. baumannii is grown in human serum albumin (HSA), this pathogen responds by modifying the expression of critical genes 10 – 16 , such as those related to iron uptake systems and resistance to β-lactams 17 . Another effect that was observed in these conditions is an increase in the minimum inhibitory concentrations (MICs) to cefiderocol (CFDC), a novel antibiotic approved by Food and Drug Administration ( https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209445s000lbl.pd ).…”

“…Since CFDC is a cephalosporin antibiotic conjugated to a siderophore, transport into the bacterial periplasm to inactivate penicillin binding proteins (PBPs) depends on receptors regulated by the iron concentration in the milieu. An attractive hypothesis to explain these results is that when A. baumannii grows in the presence of HSA-containing human fluids, there is down-regulation the expression of iron uptake system genes, reducing the ability of CDFC to reach the cell’s PBPs 17 . Since albumin is absent or present in trace concentrations in normal HU, we hypothesize that CFDC efficacy would not be reduced when A. baumannii is exposed to HU.…”