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

Casin Le,Brent Nishimura,Luis A Actis,Maria Soledad Ramírez,Camila Pimentel,Marcelo E Tolmasky,Marisel R Tuttobene,Vyanka Mezcord,Alejandro J Vila,Fernando Pasteran,Robert A Bonomo,Jenny Escalante,Susana Arriaga,Tomás Subils,Aimee Carranza,Alejandra Corso

doi:10.3390/biomedicines10030600

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.

Highlights

Carbapenem-resistant Acinetobacter baumannii (CRAB), one of the most feared pathogens in healthcare settings, has been categorized by the Centers for Disease Control and Prevention (CDC) as an “urgent threat” [1–5]
Changes in the Expression Levels of Genes Associated with Iron Uptake Systems in the Presence of Human Fluids
TonB-dependent receptor pirA, piuA, and bauA, were carried out using total RNA extracted from cells cultured in lysogeny broth (LB), LB supplemented with 4% HPF and 3.5% HSA, and cells cultured in 100% HS, as previously described [47]

Summary

Introduction

Carbapenem-resistant Acinetobacter baumannii (CRAB), one of the most feared pathogens in healthcare settings, has been categorized by the Centers for Disease Control and Prevention (CDC) as an “urgent threat” [1–5]. CFDC is a hybrid molecule that consists of a cephalosporin component that targets cell wall synthesis and a catechol siderophore moiety that allows cell penetration by active ferric-siderophore transporters [21–25]. This novel synthetic compound uses a “Trojan horse” strategy to improve antibiotic penetration and reach a high concentration at the target site [22,23]. This strategy allows the drug to enter the bacterial cells using active iron transporters. In A. baumannii, the most well-characterized iron transporters are bauA, bfnH, and fbsN, which are coupled to a

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