(197a) The Triggered Delivery of Polymyxin Antibiotics from Polyelectrolyte Microgels

One form of a self-defensive infection-resisting surface sequesters an antimicrobial within a coating until a bacterial challenge triggers release. The trigger is highly localized and can be caused by acid or enzyme secretion due to bacterial metabolism or simply by local thermodynamic changes induced by the highly anionic nature of a bacterial envelope. We are developing self-defensive surfaces using polyanionic microgels which can be electrostatically deposited onto almost any surface to form a sub-monolayer coating. Loading occurs by a subsequent self-assembly step where multivalent antimicrobial macro-cations complex within the polyanionic microgels. We have found that a broad variety of cationic molecules can be loaded from low-ionic-strength buffer where the electrostatic shielding effects of Na⁺ are small. We have shown (1), for example, that colistin (polymyxin E; +5) can be electrostatically loaded from low-salt buffer into microgels made of poly(acrylic acid) (PAA), remain sequestered there for weeks, and kill E. coli on contact when exposed to a bacterial challenge. However, the colistin is released in an ineffective burst when the ionic strength of the surrounding buffer is increased to 0.14 M, because Na⁺ shielding interferes with the colistin/PAA complexation. In contrast, the L5 (+6, 2274 Da) and Sub5 (+7, 1723 Da) antimicrobial peptides both remain sequestered in PAA under physiological conditions and are able to create surfaces that are self-defensive against staphylococci.

With the objective of creating self-defensive surfaces using FDA-approved antibiotics, we are working to identify the key properties that control microgel/antibiotic complexation and, thus, the ability of microgels to sequester and release their antibiotic payload. Here we focus on polymyxin B and E and their complexation with poly(styrene sulfonate) (PSS) microgels. We follow loading and sequestration using time-resolved optical microscopy to measure microgel deswelling/swelling in a continuous flow chamber that provides precise control over pH, ionic strength, and antibiotic concentration. Recent work (2) has shown that the PSS/colistin complexation strength is greater than the PAA/colistin complexation strength, an effect demonstrated by coarse-grain molecular dynamics simulations to be caused by the presence of the pendant phenyl rings along the PSS backbone. Except for a phenyl ring that substitutes for a dimethyl group, polymyxin B is chemically identical to colistin, yet we find that the threshold [Na⁺] in phosphate buffer to trigger release (de-complexation) is 0.216 M for colistin and 0.516 M for polymyxin B release, again indicating that aromaticity plays an important role in complexation and antibiotic sequestration. This finding has important implications on how each of these antibiotics might be incorporated into a self-defensive technology, and work continues to assess the interactions of polymyxin-loaded PSS microgels with gram-negative bacteria.

(1) J. Liang, H. Wang, and M. Libera, Biomaterial Surfaces Self-Defensive against Bacteria by Contact Transfer of Antimicrobials.Biomaterials, 2019. 204(June): p. 25-35.

(2) X. Xiao, J. Ji, W. Zhao, S. Nangia, and M. Libera. Salt Destabilization of the Complexation of Cationic Colistin within Polyanionic Microgels, submitted to Macromolecules, 2021.