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Choline-Functionalized Supramolecular Copolymers: Toward Antimicrobial Activity against Streptococcus pneumoniae.

ABSTRACT: Dynamic binding events are key to arrive at functionality in nature, and these events are often governed by electrostatic or hydrophobic interactions. Synthetic supramolecular polymers are promising candidates to obtain biomaterials that mimic this dynamicity. Here, we created four new functional monomers based on the benzene-1,3,5-tricarboxamide (BTA) motif. Choline or atropine groups were introduced to obtain functional monomers capable of competing with the cell wall of Streptococcus pneumoniae for binding of essential choline-binding proteins (CBPs). Atropine-functionalized monomers BTA-Atr and BTA-Atr₃ were too hydrophobic to form homogeneous assemblies, while choline-functionalized monomers BTA-Chol and BTA-Chol₃ were unable to form fibers due to charge repulsion. However, copolymerization of BTA-Chol₃ with non-functionalized BTA-(OH)₃ yielded dynamic fibers, similar to BTA-(OH)₃. These copolymers showed an increased affinity toward CBPs compared to free choline due to multivalent effects. BTA-based supramolecular copolymers are therefore a versatile platform to design bioactive and dynamic supramolecular polymers with novel biotechnological properties.

SUBMITTER: Vleugels MEJ

PROVIDER: S-EPMC8672346 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Choline-Functionalized Supramolecular Copolymers: Toward Antimicrobial Activity against <i>Streptococcus pneumoniae</i>.

Vleugels Marle E J MEJ Varela-Aramburu Silvia S de Waal Bas F M BFM Schoenmakers Sandra M C SMC Maestro Beatriz B Palmans Anja R A ARA Sanz Jesús M JM Meijer E W EW

Biomacromolecules 20211130 12

Dynamic binding events are key to arrive at functionality in nature, and these events are often governed by electrostatic or hydrophobic interactions. Synthetic supramolecular polymers are promising candidates to obtain biomaterials that mimic this dynamicity. Here, we created four new functional monomers based on the benzene-1,3,5-tricarboxamide (BTA) motif. Choline or atropine groups were introduced to obtain functional monomers capable of competing with the cell wall of <i>Streptococcus pneum ...[more]

PMID: 34846847

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Project description:Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and is responsible for multiple other infectious diseases, such as meningitis and otitis media, in children. Resistance to penicillins, macrolides, and fluoroquinolones is increasing and, since the introduction of pneumococcal conjugate vaccines (PCVs), vaccine serotypes have been replaced by non-vaccine serotypes. Antisense peptide nucleic acids (PNAs) have been shown to reduce the growth of several pathogenic bacteria in various infection models. PNAs are frequently coupled to cell-penetrating peptides (CPPs) to improve spontaneous cellular PNA uptake. In this study, different CPPs were investigated for their capability to support translocation of antisense PNAs into S. pneumoniae. HIV-1 TAT- and (RXR)4XB-coupled antisense PNAs efficiently reduced the viability of S. pneumoniae strains TIGR4 and D39 in vitro. Two essential genes, gyrA and rpoB, were used as targets for antisense PNAs. Overall, the antimicrobial activity of anti-gyrA PNAs was higher than that of anti-rpoB PNAs. Target gene transcription levels in S. pneumoniae were reduced following antisense PNA treatment. The effect of HIV-1 TAT- and (RXR)4XB-anti-gyrA PNAs on pneumococcal survival was also studied in vivo using an insect infection model. Treatment increased the survival of infected Galleria mellonella larvae. Our results represent a proof of principle and may provide a basis for the development of efficient antisense molecules for treatment of S. pneumoniae infections. IMPORTANCE Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and is responsible for the deaths of up to 2 million children each year. Antibiotic resistance and strain replacement by non-vaccine serotypes are growing problems. For this reason, S. pneumoniae has been added to the WHO "global priority list" of antibiotic-resistant bacteria for which novel antimicrobials are most urgently needed. In this study, we investigated whether CPP-coupled antisense PNAs show antibacterial activity in S. pneumoniae. We demonstrated that HIV-1 TAT- and (RXR)4XB-coupled antisense PNAs were able to kill S. pneumoniae in vitro. The specificity of the antimicrobial effect was verified by reduced target gene transcription levels in S. pneumoniae. Moreover, CPP-antisense PNA treatment increased the survival rate of infected Galleria mellonella larvae in vivo. Based on these results, we believe that efficient antisense PNAs can be developed for the treatment of S. pneumoniae infections.

Dataset Information

Choline-Functionalized Supramolecular Copolymers: Toward Antimicrobial Activity against Streptococcus pneumoniae.

Publications

Choline-Functionalized Supramolecular Copolymers: Toward Antimicrobial Activity against <i>Streptococcus pneumoniae</i>.

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