Design of a novel class of dynamic polymers with antimicrobial potential

The group of Dr. Jesús M. Sanz in the Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), in collaboration with the laboratory of Prof. Bert Meijer, from the Institute for Complex Molecular Systems of the Eindhoven University of Technology (The Netherlands), has published a study in the Biomacromolecules journal that presents the antimicrobial activity on the respiratory pathogen Streptococcus pneumoniae (pneumococcus) of a novel polymer type based on benzene tricarboxamide monomers (BTA).

Contrary to the most usual polymers, BTA monomers do not covalently bind among themselves, but they pile up through weaker interactions of hydrophobic and hydrogen bonding nature. The outcome is microfibres in which the monomers are in a continuous process of dissociation and association, so that the monomers may eventually "walk" along with the fiber and locally cluster together if they find another molecular entity that attracts them.

In this work, copolymers of both basic and chemically choline-functionalized BTA monomers were employed with the aim of searching for efficient interaction with the so-called choline-binding proteins (CBPs) of the pneumococcal surface. CBPs are essential proteins for the viability and virulence of this pathogen, and they need, for their biological activity, to recognize the choline residues present in the bacterial cell wall, so the BTA-choline fibers were designed to "scavenge" them through a competitive interaction.

Vleugels et al. have revealed, through biophysical experiments, that although the starting copolymer contained the BTA-choline monomers randomly distributed along with the fiber, in the presence of the choline-binding module of the LytA CBP such monomers rearranged around the protein, allowing an interaction around 2500-fold higher than free choline. These chemical multivalent effects surpass those produced by other similar, albeit less dynamic, nanoparticles such as dendrimers.

Once the capacity of interaction with their target was demonstrated, the microfibres were added to pneumococcal cultures, inducing bacterial cell chaining instead of the usual diplococcal morphology, presumably due to the inhibition of CBPs involved in daughter cell separation upon division, such as the LytB hydrolase. Multivalent effects were also evident, since a 1700-fold lower concentration compared to free choline was needed for a similar physiological effect. Previous studies have demonstrated that this chaining is bound to lower infectivity and increased bacterial phagocytosis, so therefore these fibers may pave the way for the design of novel non-lytic antimicrobials that induce the response of the immune system of the individual.

The study also opens up the way for the use of these dynamic BTA polymers in highly efficient cell recognition systems through their functionalization with proteins that bind to the cellular surface, leading to novel diagnostic tools.

Prof. Meijer will give a talk in the CIB-CSIC next 27 May in the framework of the Master in Integrative Synthetic Biology (MISB), where he will explain the latest advances of these supramolecular structures and their application in Biology.

Reference: Choline-functionalized supramolecular copolymers: towards antimicrobial activity against Streptococcus pneumoniae. Vleugels M, Varela-Aramburu S, Schoenmakers S, Maestro B, Palmans A, Sanz JM*, Meijer EW* (2021) Biomacromolecules 22, 5363-5373. https://pubs.acs.org/doi/10.1021/acs.biomac.1c01293