On the ionophoric selectivity of nonactin and related macrotetrolide derivatives

Abstract

Nonactin and its analogs constitute a central class of macrocycles with an antibiotic activity closely related to their selective ionophoric behavior. In this study, we apply experimental and computational methods to revisit the specificity of cation binding and transport by three nactin variants differing in structural properties, such as the position of the ester linkages, the nature of the side groups, or the flexibility of the backbone. On the one hand, electrospray ionization mass spectrometry and infrared spectroscopy are employed to expose the selectivity of the liquid-liquid (water-chloroform) extraction of alkali cations by nonactin and to demonstrate that the cation complexes are partially hydrated in the organic phase. Furthermore, laser desorption mass spectrometry is employed to determine the intrinsic cation affinities of nonactin under solvent-free conditions. On the other hand, density functional theory calculations are performed to characterize the conformations of the alkali cation complexes of the three nactins, and to assess the role of intermolecular and solvent interactions in determining their relative stability. Depending on the structure of the macrocycle, the cation complexes adopt either a cage-like conformation or a tweezer-like conformation. The computations show that the partial hydration of those different conformations in the organic phase, determine the distinct cation extraction selectivities that are observed experimentally.

Isolated alkali cation complexes of the antibiotic ionophore nonactin: correlation with crystalline structures

“…1. A recent study has assessed a relevant role in the observed behavior to the microhydration of the nactin complexes in the organic phases, 15 thereby corroborating an old idea introduced in the early investigations on these systems. 16 Also remarkably, the chirality of the nonactin building units and their sequence in the macrocycle has been shown to have a relevant influence on the selectivity of cation binding.…”

Genome Mining of the Marine Actinomycete Streptomyces sp. DUT11 and Discovery of Tunicamycins as Anti-complement Agents

“…Nonactin and related analogs are a central class of macrocyclic ionophores consisting of 32-membered ring (a cyclodotricontane) built with 24 carbon and 8 oxygen atoms ( Martinez-Haya et al, 2017 ). These compounds show antibiotic, antitumor and anti-virus activities and are also widely used for the preparation of ion-selective electrodes and sensors ( Zhan and Zheng, 2016 ).…”

Inclusion complexes of the macrocycle nonactin with benchmark protonated amines: aniline and serine

“…[19][20][21][22][23] Most investigations of the inclusion complexes of nonactin have focused on its highly efficient binding of metal cations and ammonium. 11,16,[24][25][26][27][28][29][30][31][32][33][34][35][36][37] Ammonium builds a specific tetrapodal coordination with the ether oxygen atoms of the four oxolane rings, which turns out to be significantly more stable than the analogous coordination with the oxygen atoms of the ester moieties. Whereas the supramolecular activity of nonactin may extend to complex amines matching the cavity size, a limited number of studies have actually considered molecular cations beyond ammonium.…”