Anti-bacterial β-cyclodextrin derivatives inspired by the antimicrobial peptide polymyxin

Posted by

Polymyxin-like b-CD derivatives were created by incorporating seven cationic amino groups and a hydrophobic alkyl chain tail into the b-CD molecule. Membrane-active compounds such as anti-microbial peptides, must have both cationic and hydrophobic moieties in order to interact with membrane lipid phosphate and the inside of the lipid membrane. When we need to provide enough hydrophobicity to the molecule, introducing a single hydrophobic chain tail locally, as seen in polymyxins, may be important to express bacterial membrane-disrupting ability and lead to selective anti-bacterial activity. Anti-bacterial properties of C16-modified noAcb-CD 17 and C12-modified Acb-CD 24 against drug-resistant pathogens were demonstrated in preliminary experiment. Compound 17 is anti-bacterial against MRSA (MIC 12 mM) and carbapenemase-producing P. aeruginosa (MIC 24 mM), but the b-CD is inactive against Expanded spectrum b-lactamase-producing and carbapenemase-producing E. coli strain (MIC 447 mM). In the case of 24, it was active against MRSA (MIC, 19 mM) and carbapenemase-producing P. aeruginosa (9 mM). Furthermore, it inhibited the growth of both Expanded spectrum b-lactamase-producing E. coli and carbapenemase producing E. coli (MIC, 9 and 5 mM). As seen in polymyxin analogues with a longer fatty chain tail than natural polymyxin, the b-CDs were anti-bacterial to both Gram-positive and Gram-negative bacteria. It may be the results of strong electrostatic interaction and hydrophobic interaction by poly-amino groups and a long alkyl group. In order to express polymyxin-like antiGram negative bacteria-selective activity, we may change the number of amino groups and simultaneously change the length of chain tail of b-CD derivatives to adjust balance between hydrophilicity (cationic property) and hydrophobicity to interact with the bacterial membrane as that of the polymyxins. Polymyxins are important for the treatment of infectious deceases caused by multidrug-resistant Gram-negative bacteria. Their anti-bacterial mechanism of destroying membrane integrity is orthogonal to that of conventional antibiotics which target bacterial cell biosynthetic pathways, and thus the peptides have become useful in combating drug-resistant pathogens. The b-CD with an alkyl chain tail had antibacterial properties similar to polymyxins and their analogues. As a result, peptide-like membrane-disrupting b-CD derivatives may be worth further investigation in order to better understand polymyxins and develop novel anti-bacterial drugs to combat with multidrug-resistant bacterial infections.

Hatsuo Yamamura, Masashi Owaki, Kana Isshiki, Yukari Ishihara, Hisato Kato, Takashi Katsu, Kazufumi Masudab Kayo Osawa and Atsushi Miyagawa: Anti-bacterial β-cyclodextrin derivatives inspired by the antimicrobial peptide polymyxin in order to better understand the role of single hydrophobic chain tail in selective anti-bacterial activity. New J. Chem., 2023,47, 10921-10929.

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.