We describe the synthesis of pro-antimicrobial networks via degradable acetals (PANDAs) as a new paradigm for sequestration and triggered release of volatile, bioactive aldehydes. PANDAs derived from diallyl p-chlorobenzaldehyde acetal degrade and release p-chlorobenzaldehyde as an antibacterial and antifungal agent under mild conditions (pH 7.4/high humidity). We show that PANDAs enable facile access to materials with tunable release profiles, potent antimicrobial activity without triggering antimicrobial resistance, and minimal cytotoxicity.
With the increasing number of patients prescribed immunosuppressants coupled with the rise in antibiotic resistance - life-threatening microbial infections are a looming global threat. With limited success within the antibiotic pipeline, nature-based essential oils (EOs) are being investigated for their multimodal effectiveness against microbes. Despite the promising potential of EOs, difficulties in their encapsulation, limited water solubility, and high volatility limit their use. Various studies have shown that covalent attachment of these EO derivatives to polymers can mitigate these limitations. The current study presents the synthesis of a fully-degradable, sustained release, cytocompatible, pro-antimicrobial acetal network derived from p-anisaldehyde. This polymer network design provides a pathway toward application-specific EO releasing materials with quantitative encapsulation efficiencies, sustained release, and broad-spectrum antimicrobial activity.
We describe the design and synthesis of degradable, dual-release, pro-antimicrobial poly(thioether acetal) networks derived from synergistic pairs of aromatic terpene aldehydes. Initially, we identified pairs of aromatic terpene aldehyde derivatives exhibiting a synergistic antimicrobial activity against Pseudomonas aeruginosa by determining fractional inhibitory concentrations. Synergistic aldehydes were converted into dialkene acetal monomers and copolymerized at various ratios with a multifunctional thiol via thiol−ene photopolymerization. The stepgrowth nature of the thiol−ene polymerization ensures every crosslink junction contains a degradable acetal linkage enabling a fully cross-linked polymer network to revert into its small molecule constituents upon hydrolysis, releasing the synergistic aldehydes as active antimicrobial compounds. A three-pronged approach was used to characterize the poly(thioether acetal) materials: (i) determination of the degradation/aldehyde release behavior, (ii) evaluation of the antimicrobial activity, and (iii) identification of the cellular pathways impacted by the aldehydes on a library of mutated bacteria. From this approach, a polymer network derived from a 40:60 p-bromobenzaldehyde/p-anisaldehyde monomer ratio exhibited potent antimicrobial action against Pseudomonas aeruginosa, a common opportunistic human pathogen. From a transposon mutagenesis assay, we showed that these aldehydes target porins and multidrug efflux pumps. The aldehydes released from the poly(thioether acetal) networks exhibited negligible toxicity to mammalian tissue culture cells, supporting the potential development of these materials as dual-release antimicrobial biomaterial platforms.
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