Selective synthesis of N,N,N-trimethylated chitosan derivatives at different degree of substitution and investigation of structure-activity relationship for activity against P. aeruginosa and MRSA

Abstract

Two new cationic chitosan derivatives were synthesized using a combination of Boc and TBDMS protection strategies. This included a series of six samples of the TMC_NH2/TM derivative, where some of the amino groups were N,N,N-trimethylated and the remaining was in the primary state. A series of six samples of the TACin derivative, where some of the amino groups were N-acetylated with quaternary 2-(N,N,N-trimethylammoniumyl) acetyl group and the remaining fully N-acetylated, were also synthesized. The degree of substitution (DS) for quaternary amino groups in these series ranged from 0.06-0.89. TMC_DM/TM derivatives with a mix of N,N,N-trimethylated and N,N-dimethylated groups were also synthesized according to a published procedure but in this case, it was more difficult to control the DS than with the TBDMS protection strategy. Broth microdilution assay revealed a markedly different structure-activity relationship (SAR) for the two derivatives. The activity for the TMC derivatives reached a plateau above 0.2-0.3 DS whereas the activity increased continuously with DS for TACin. The highest DS TMC_NH2/TM was more active than the highest DS, TACin, against Gram-positive MRSA but less active against the Gram-negative P. aeruginosa.

Keywords: Antimicrobial; Cationic; Chitosan derivatives; Conjugation; Methicillin-resistant Staphylococcus aureus; Pseudomonas aeruginosa.