Thiocillin and Micrococcin Exploit the Ferrioxamine Receptor of<i>Pseudomonas aeruginosa</i>for Uptake

ABSTRACTThiopeptides are a class of Gram-positive antibiotics that inhibit protein synthesis. They have been underutilized as therapeutics due to solubility issues, poor bioavailability, and lack of activity against Gram-negative pathogens. We discovered recently that a member of this family, thiostrepton, has activity againstPseudomonas aeruginosa and Acinetobacter baumanniiunder iron-limiting conditions. Thiostrepton uses pyoverdine siderophore receptors to cross the outer membrane, and combining thiostrepton with an iron chelator yielded remarkable synergy, significantly reducing the minimal inhibitory concentration. These results led to the hypothesis that other thiopeptides could also inhibit growth by using siderophore receptors to gain access to the cell. Here, we screened six thiopeptides for synergy with the iron chelator deferasirox againstP. aeruginosaand a mutant lacking the pyoverdine receptors FpvA and FpvB. Our findings suggest that thiopeptides such as thiocillin cross the outer membrane using FoxA, the ferrioxamine siderophore receptor. Other structurally related thiopeptides did not inhibit growth ofP. aeruginosa, but had greater potency against methicillin-resistantStaphylococcus aureusthan thiostrepton and related thiopeptides. These results suggest that thiopeptide structures have evolved with considerations for target affinity and entry into cells.

Thiocillin and Micrococcin Exploit the Ferrioxamine Receptor ofPseudomonas aeruginosafor Uptake Journal Articles