Broad-Spectrum Bactericidal Activity of a Synthetic Random Copolymer Based on 2-Methoxy-6-(4-Vinylbenzyloxy)-Benzylammonium Hydrochloride

Abstract

Low-molecular-weight organic ammonium salts exert excellent antimicrobial effects by interacting lethally with bacterial membranes. Unfortunately, short-term functionality and high toxicity limit their clinical application. On the contrary, the equivalent macromolecular ammonium salts, derived from the polymerization of monomeric ammonium salts, have demonstrated improved antibacterial potency, a lower tendency to develop resistance, higher stability, long-term activity, and reduced toxicity. A water-soluble non-quaternary copolymeric ammonium salt (P7) was herein synthetized by copolymerizing 2-methoxy-6-(4-vinylbenzyloxy)-benzylammonium hydrochloride monomer with N, N-di-methyl-acrylamide. The antibacterial activity of P7 was assessed against several multidrug-resistant (MDR) clinical isolates of both Gram-positive and Gram-negative species. Except for colistin-resistant Pseudomonas aeruginosa, most isolates were susceptible to P7, also including some Gram-negative bacteria with a modified charge in the external membrane. P7 showed remarkable antibacterial activity against isolates of Enterococcus, Staphylococcus, Acinetobacter, and Pseudomonas, and on different strains of Escherichia coli and Stenotrophomonas maltophylia, regardless of their antibiotic resistance. The lowest minimal inhibitory concentrations (MICs) observed were 0.6–1.2 µM and the minimal bactericidal concentrations (MBC) were frequently overlapping with the MICs. In 24-h time–kill and turbidimetric studies, P7 displayed a rapid non-lytic bactericidal activity. P7 could therefore represent a novel and potent tool capable of counteracting infections sustained by several bacteria that are resistant to the presently available antibiotics.

Bactericidal Activity of a Self-Biodegradable Lysine-Containing Dendrimer against Clinical Isolates of Acinetobacter Genus

“…The structure of G5-PDK was designed based on the recent results obtained by us concerning cationic copolymers and cationic amino acids-modified polyester-based dendrimers [ 27 , 28 , 29 , 31 ]. We observed significant differences between the antibacterial activity of the cationic copolymers [ 29 , 31 ] and that of the cationic dendrimers [ 27 , 28 ]. While cationic copolymers showed broad-spectrum activity against most of the 61 tested MDR isolates [ 29 , 31 ], belonging to both Gram-positive and Gram-negative species, cationic dendrimers showed high specificity for some families of bacteria.…”

“…We observed significant differences between the antibacterial activity of the cationic copolymers [ 29 , 31 ] and that of the cationic dendrimers [ 27 , 28 ]. While cationic copolymers showed broad-spectrum activity against most of the 61 tested MDR isolates [ 29 , 31 ], belonging to both Gram-positive and Gram-negative species, cationic dendrimers showed high specificity for some families of bacteria. We assumed that the random and not-controlled structure of copolymers, and the cationic charge randomly distributed along the whole polymer backbone, could translate in a higher multivalency, associated to a higher adaptability (intended as capability to interact with) to different types of bacterial surfaces.…”

“…Antibacterial Activity of G5-PDK 2.6.1. Design of the Structure of G5-PDK The structure of G5-PDK was designed based on the recent results obtained by us concerning cationic copolymers and cationic amino acids-modified polyester-based dendrimers [27][28][29]31]. We observed significant differences between the antibacterial activity of the cationic copolymers [29,31] and that of the cationic dendrimers [27,28].…”

“…Natural AMPs have shown high potential to replace conventional and no longer effective antibiotics. Being highly susceptible to inactivation by peptidases, for years AMPs have inspired the synthesis of more stable antibacterial cationic materials, including stabilized peptides, enantiomeric peptides not susceptible to proteolysis, positively charged polymers, copolymers, and dendrimers [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Generally, synthetic macromolecules, such as polymers and dendrimers, compared to natural AMPs or low molecular weight (MW) peptides, have the advantages of possessing better antibacterial potency, a lower tendency to develop resistance, greater stability, long-term activity, and reduced toxicity [ 25 ].…”

“…Generally, synthetic macromolecules, such as polymers and dendrimers, compared to natural AMPs or low molecular weight (MW) peptides, have the advantages of possessing better antibacterial potency, a lower tendency to develop resistance, greater stability, long-term activity, and reduced toxicity [ 25 ]. Although these compounds may also act via specific mechanisms, such as inhibiting protein synthesis, DNA replication, the synthesis of cell wall, or inducing cell apoptosis and necrosis, the main recognized mechanism to explain their antimicrobial activity is an irreversible, non-receptor mediated, damage to microbial membranes, leading to lytic or non-lytic bacterial death [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”