Complexes formed by the siderophore-based monosulfactam antibiotic BAL30072 and their interaction with the outer membrane receptor PiuA of P. aeruginosa

The Role of Iron and Siderophores in Infection, and the Development of Siderophore Antibiotics

“…The molar ratio of cefiderocol to ferric iron in the equilibrium complex was found to be 1:1 [108], lower than the expected 3:1 reported for monocarbams [117]. It seems likely that, as observed with BAL30072 [118], other parts of the molecule provide secondary ligands to fulfill the coordination requirements of the ferric ion. The example of BAL30072 strongly suggests that a lower stoichiometry might be the one recognized by the receptor, so that to focus only on the highest stoichiometry might be misleading for siderophores with fewer than 6 donors.…”

Design, synthesis and biological evaluation of novel DNA gyrase inhibitors and their siderophore mimic conjugates

“…(Figure 1) has been found to form compact complex in solution comprising two BAL30072 molecules and one Fe 3+ ion. In this complex sulfate group of BAL30072 participates as a chelating functionality in addition to the dihydroxypyridone moiety [30]. In another study with (pre)acinetobactin, a siderophore secreted by A. baumannii, the same ligand to metal stoichiometry in the solution was found to be favorable in low iron conditions and such complex is readily recognized and transported by the outer membrane (OM) transporter into the periplasm of A. baumannii.…”

“…The catechol siderophore mimic was attached via two different substitution patterns, to obtain either 3,4-dihydroxyphenyl-based or 2,3-dihydroxyphenyl-based conjugates. To compare the effects of the siderophore moiety on DNA gyrase inhibition, the compounds were also prepared with free amino (11,12,29,30) or acetamido (13,14,(18)(19)(20)(21)(22)(23) groups.…”

“…These data suggest that efflux problems, but not cell wall penetration, remain the issue in terms of the weak antibacterial activities of the 4,5,6,7tetrahydrobenzo[d]thiazole derivatives. Recent studies revealed that not only siderophore-mimic moieties, but also other groups present in the molecule could contribute to iron chelation [30,31]. For example, BAL30072…”

Glucose transport via the pseudomonad porin OprB: implications for the design of Trojan Horse anti-infectives

“…8 To overcome this issue, siderophore receptors have been proposed as potential gateway within the so-called Trojan Horse strategy: [9][10][11] molecules able to bind iron and structurally similar to natural substrates can be transported inside bacteria and act as a vector/cargo of antibacterial activity. 12,13 However, siderophore receptors 14 undergo conformational changes during transport and require energy to function, with a limitation on the transport rate. Here we propose and demonstrate the same Trojan Horse strategy considering only specific channels functioning on passive transport, not requiring energetically-driven large conformational changes for transport of molecules.…”