PAMAM dendrimers with dual-conjugated vancomycin and Ag-nanoparticles do not induce bacterial resistance and kill vancomycin-resistant Staphylococci

The effective life-time of new antimicrobials until the appearance of the first resistant strains is steadily decreasing, which discourages incentives for commercialization required for clinical translation and application. Therefore, development of new antimicrobials should not only focus on better and better killing of antimicrobial-resistant strains, but as a paradigm shift on developing antimicrobials that prevent induction of resistance. Heterofunctionalized, poly-(amido-amine) (PAMAM) dendrimers with amide-conjugated vancomycin (Van) and incorporated Ag nanoparticles (AgNP) showed a 6-7 log reduction in colony-forming-units of a vancomycin-resistant Staphylococcus aureus strain in vitro, while not inducing resistance in a vancomycin-susceptible strain. Healing of a superficial wound in mice infected with the vancomycin-resistant S. aureus was significantly faster and more effective by irrigation with low-dose, dual-conjugated Van-PAMAM-AgNP dendrimer suspension than by irrigation with vancomycin in solution or a PAMAM-AgNP dendrimer suspension. Herewith, dual-conjugation of vancomycin together with AgNPs in heterofunctionalized PAMAM dendrimers fulfills the need for new, prolonged life-time antimicrobials killing resistant pathogens without inducing resistance in susceptible strains. Important for clinical translation, this better use of antibiotics can be achieved with currently approved and clinically applied antibiotics, provided suitable for amide-conjugation.

Statement of significance

Stringent regulations, high development costs and shorter effective life-times of new antimicrobials before the first resistant strains appear, make development of new antimicrobials commercially little attractive. Considering the steadily shortening effective life-time of novel antibiotics, development of novel antimicrobials should focus on infection-control strategies that kill infectious bacteria without inducing bacterial antimicrobial-resistance. The heterofunctionalized dual-antimicrobial dendrimers described in this study, killed vancomycin-resistant staphylococci, while not inducing resistance in a vancomycin-susceptible strain. Significantly, these heterofunctionalized dendrimers can be prepared with currently available antibiotics. Therewith they allow to make better use of existing antibiotics, provided amenable to amideconjugation and their pathway to clinical translation is short. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd.