Acinetobacter baumannii has raised particular concern due to the increased occurrence of resistance in Acinetobacter species to last-resort antibiotics. Virulent strains show decreased cell permeability, compounded with the inherent impermeable cell wall of this Gram-negative bacteria, it is challenging to develop an antibiotic to treat A. baumannii. Acinetobacter infections have been identified by the CDC as an urgent threat, but few antibiotics are being developed. Instead, methods to use current antibiotics and bypass resistance mechanisms are being researched. Siderophores have been identified as possible vectors to smuggle antibiotics past the impermeable cell wall. The virulence of Gram-negative bacteria has also been linked to the iron scavenging siderophore transport system. A. baumannii uses three siderophores to chelate iron and transport it into the cytoplasm; acinetobactin, baumannoferrin, and fimsbactin. While baumannoferrin and fimsbactin are able to sequester iron, recent studies have shown that pre-acinetobactin/acinetobactin is the only siderophore required for virulence. The significance of acinetobactin and the active transport of iron bound siderophores has identified acinetobactin as a target for a siderophore-antibiotic conjugate. Also known as a “Trojan-horse”, a siderophore-antibiotic conjugate uses the active transport pathway of the siderophore to deliver the antibiotic to either the periplasmic space or the cytoplasm. Previous work has identified three possible linkage positions that should allow active transport to continue. This work shows synthetic routes to pre-acinetobactin analogues with linkers to further functionalize with antibiotics.

Functionalized pre-acinetobactin for siderophore-antibiotic conjugates

ACS Spring Meeting 2021

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