Biomimetic ferrichrome: structural motifs for switching between narrow- and broad-spectrum activities in P. putida and E. coli

Abstract

A series of novel ferrichrome (FC) analogs was designed based on the X-ray structure of FC in the FhuA transporter of Escherichia coli. Two strategies were employed: the first strategy optimized the overall size and relative orientation of H-bonding interactions. The second strategy increased H-bonding interactions by introducing external H-donors onto analogs' backbone. Tris-amino templates were coupled to succinic or aspartic acid, and the second carboxyl was used for hydroxamate construction. Succinic acid provided analogs without substituents, whereas aspartic acid generated analogs with external amines (i.e. H-donors). All analogs had similar physicochemical properties, yet the biological activity in Pseudomonas putida and E. coli showed great variation. While some analogs targeted specifically P. putida, others were active in both strains thus exhibiting broad-spectrum activity (as in native FC). Narrow-spectrum or species-specificity might find application in microbial diagnostic kits, while broad-spectrum recognition may have advantages in therapeutics as siderophore-drug conjugates. The differences in the structure and range of microbial recognition helped us in formulating guidelines for minimal essential parameters required for inducing broad-spectrum activity.

Thermodynamic Stability and Speciation of Ga(III) and Zr(IV) Complexes with High-Denticity Hydroxamate Chelators

“…For each ligand, the protonation constants were assigned by comparing them with the known protonation constants of hydroxamate ligands. 24 , 35 , 37 , 42 When the changes in temperature, ionic strength, and ligand structures are allowed for, the protonation constants of H 3 L1 and H 4 L2 are in excellent agreement with the literature values of the cyclic hydroxamate siderophore DFOE (log K 1 = 9.89, log K 2 = 9.42, and log K 3 = 8.65) reported by Anderegg et al 37 The pH-dependent UV–vis titrations of H 3 L1 and H 4 L2 ( Figure S1 ) revealed the development of a strong band with λ max = 230 nm, when the pH was increased from 7 to 11, which is usually observed for a hydroxamic group deprotonation process. 24 , 43 The amino group protonation of H 4 L2 was not detectable in the experimental pH range.…”

“…In addition, the physicochemical properties of Zr(IV) complexes with three further trihydroxamic ligands, i.e. H 3 L3 (FOXE 2-5), 38 H 3 L4 (T4), 35 and DFOE ( Scheme 1 ), were also investigated for the sake of comparison. The ligands employed here were selected to investigate the influence of some structural elements on the physicochemical properties of Zr(IV) complexes: i.e., (i) the number of binding groups required to complete the coordination sphere of the metal cation; (ii) the possible advantage of the macrocyclic effect; (iii) the size of the ligand cavity, which should be large enough to minimize ring strain; (iv) the symmetry of the ligand, which could limit the probability of a complex challenge.…”

Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets

“…Although enantiomers of β‐amino acid, tripods 3 and 5 , display a distinct chirality pattern around the iron, for γ‐amino acid analogue 4 at the same concentration only a trace signal was observed in the ligand‐to‐metal charge transfer (LMCT) region of the iron complex (data not shown) . Such decrease in chiral preference around the iron with increasing linker length has been previously observed in transition from α to β oriented hydroxamates as well . The chiral center of β and γ amino acids is decoupled from the hydroxamates by one or two methylene spacers.…”

“…Thus, replacing α‐amino acid hydroxamates with their β and γ equivalents tackles both complementary approaches simultaneously: introducing polar substituents for enhanced hydrogen bonding to the transporter, yet moving them further away from the metal‐binding site. A recent example of analogues with β positioned hydroxamates indicates a significant potential of this approach …”

Cyclic Analogs of Desferrioxamine E Siderophore for 68Ga Nuclear Imaging: Coordination Chemistry and Biological Activity in Staphylococcus aureus

“…The m / z values obtained in MS experiments were successfully employed by our research group on numerous occasions. 52 , 53 A few major peaks characterized the MS spectra of the investigated solutions of the Fe(ClO 4 ) 3 /ligand and Ga(ClO 4 ) 3 /ligand with a 1:1 ratio ( Figure S2 ). The peaks were attributed to the mononuclear species ( Table S2 , Table S3 ), and no peaks corresponding to the free ligand were present.…”