The rapid increase of antimicrobial resistance forces researchers to find new therapeutic molecules for replacing the available antibiotics, no longer effective.
Recently, we reported the antibacterial activity against Gram-negative species, including multi-drugs-resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii, of some amino acids-modified cationic dendrimers (CDs) [1]. The lysine-containing dendrimer displayed very low MIC values, thus establishing the key role of lysine in conferring a potent antibacterial activity to the devices [1]. In order to develop new antibacterial agents active against other resistant bacterial species, we reconsidered six cationic dendrimer complexes (UOACDs), synthesized to make water-soluble and administrable in vivo a mixture of ursolic and oleanolic acids (UOA) [2, 3]. Due to their cationic features and to the presence of UOA, known for having antibacterial properties particularly against Gram-positive species [4,5], the UOACDs were considered excellent candidates to achieve the goal. We selected three UOACDs, having particle size and drug loading in the ranges of 16.1-24.9 nm and 5.0-12.7 % (wt/wt) respectively, and their antibacterial behavior was preliminary assessed against Escherichia coli and Klebsiella pneumoniae, establishing their inactivity on these species. Otherwise, UOACDs displayed significant antibacterial activity against 12 strains of the genera Enterococcus and Staphylococcus. To clarify UOA contribute to the antibacterial effects observed, free UOA was also investigated. Interestingly, it was established that the antibacterial activity reported for UOACDs, depended strongly on the number of cationic groups and on the type of amino acids present on CDs, and that it was attributable only to the CDs themselves and not to the presence of UOA. Lysine was critical for the antibacterial potency, whereas arginine was pivotal for redirecting the activity against Gram-positive species. A high cationic character, associated with a balanced lysine/arginine content, resulted in high antimicrobial effects (MICs = 0.5-8.7 µM). More in-depth investigations are underway to better define the antibacterial characteristics of the developed arginine-containing CDs.

References

1. Schito, A.M.; Alfei, S. Antibacterial activity of non-cytotoxic, amino acid-modified polycationic dendrimers against Pseudomonas aeruginosa and other non-fermenting Gram-negative bacteria. Polymers 2020, 12, 1818.
2. Bisio, A.; Romussi, G.; Russo, E.; Cafaggi, S.; Schito, A. M.; Repetto, B.; De Tommasi, N. Antimicrobial activity of the ornamental species salvia corrugata, a potential new crop for extractive purposes. Agric. Food Chem. 2008, 56, 10468−10472.
3. Alfei, S.; Taptue, G.B.; Catena, S.; et al. Synthesis of Water-soluble, Polyester-based Dendrimer Prodrugs for Exploiting Therapeutic Properties of Two Triterpenoid Acids. J. Polym. Sci. 2018, 36, 999–1010, https://doi.org/10.1007/s10118-018-2124-9.
4. Do Nascimento, P.G.; Lemos, T.L.; Bizerra, A.M.; Arriaga, Â.M.; Ferreira, D.A.; Santiago, G.M.; Braz-Filho, R.; Costa, J.G.M. Antibacterial and Antioxidant Activities of Ursolic Acid and Derivatives. Molecules 2014, 19, 1317-1327.
5. Wolska, K.I.; Grudniak, A.M.; Fiecek, B.; Kraczkiewicz-Dowjat, A.; Kurek, A. Antibacterial activity of oleanolic and ursolic acids and their derivatives. Central Eur. J. Biol. 2010, 5, 543–553, doi:10.2478/s11535-010-0045-x.