The effect of ferric Human Serum Albumin (HSA) on the Susceptibility of Acinetobacter baumannii (Ab) to Cefiderocol (CFDC)

ESCALANTE, JENNY (CO-FIRST AUTHOR); NISHIMURA, BRENT (CO-FIRST AUTHOR); TUTTOBENE, MARISEL ROMINA; SUBILS, TOMAS; MEZCORD, VYANKA; ACTIS, LUIS A.; TOLMASKY, MARCELO E.; BONOMO, ROBERT A.; RAMÍREZ, MARÍA SOLEDAD

Houston, Texas

Congreso; ASM Microbe 2023; 2023

Cefiderocol (CFDC), a chlorocathecol cephalosporin, combines inhibition of the Gram-negative bacterial cell wall synthesis with a siderophore-like moiety that facilitates entry through receptors that recognize ferric-siderophore complexes. Clinical trials showed that treating pulmonary and bloodstream Acinetobacter baumannii (Ab) infections with CFDC did not result in the same outcomes as treating other pathogens. Previous studies showed that Ab exposure to human serum albumin (HSA)-containing fluids like human pleural fluid (HPF) or human serum (HS) increases the minimal inhibitory concentration (MIC) values of CFDC. In this investigation, the effect of HSA on CFDC susceptibility and the expression of genes coding for Ab siderophore-mediated iron uptake functions was assessed. The Ab strains AB5075 and AMA40 were cultured in iron-depleted cation adjusted Mueller Hinton Broth (CAMHB), HS, and HPF, as well as in the presence of the cognate HSA-free derivatives to determine the CFDC MICs and the expression of iron-uptake associated genes. In addition, iron was removed from HSA (Fe-free HSA) and used to test phenotypic and transcriptional modifications.Removal of HSA from HPF or HS resulted in a reduction of the CFDC MICs. The presence of HSA in the media produced a decrease in levels of expression of genes coding for high-affinity iron uptake systems like pirA, piuA, bauA, and bnfH. Deferration of HSA (Fe-free HSA) was accompanied by a loss of the bacterial ability to modify the expression levels of these genes. In addition, MICs showed a decrease when iron was removed, while restored or increased values were observed when iron or HSA were added.These results indicate that the antimicrobial activity of CFDC against Ab is attenuated in the presence of iron-rich HSA-containing fluids. These observations open new avenues of investigation and the understanding of this phenomenon´s molecular mechanism will help define approaches to increase CFDC’s treatment efficiency.