Carbosilane Dendron–Peptide Nanoconjugates as Antimicrobial Agents

Abstract

Over the last decades, multidrug-resistant bacteria have emerged and spread, increasing the number of bacteria, against which commonly used antibiotics are no longer effective. It has become a serious public health problem whose solution requires medical research in order to explore novel effective antimicrobial molecules. On the one hand, antimicrobial peptides (AMPs) are regarded as good alternatives because of their generally broad-spectrum activities, but sometimes they can be easily degraded by the organism or be toxic to animal cells. On the other hand, cationic carbosilane dendrons, whose focal point can be functionalized in many different ways, have also shown good antimicrobial activity. In this work, we synthetized first- and second-generation cationic carbosilane dendrons with a maleimide molecule on their focal point, enabling their functionalization with three different AMPs. After different microbiology studies, we found an additive effect between first-generation dendron and AMP3 whose study reveals three interesting effects: (i) bacteria aggregation due to AMP3, which could facilitate bacteria detection or even contribute to antibacterial activity by preventing host cell attack, (ii) bacteria disaggregation capability of second-generation cationic dendrons, and (iii) a higher AMP3 aggregation ability when dendrons were added previously to peptide treatment. These compounds and their different effects observed over bacteria constitute an interesting system for further mechanism studies.

From Nanobiotechnology, Positively Charged Biomimetic Dendrimers as Novel Antibacterial Agents: A Review

“…Recently, Fernandez and colleagues (2019) synthetized G1 and G2 carbosilane dendrons and, using a selection of three different CAMPs, created a series of nanocomposites either by covalent links or by physical non-covalent interactions, with the aim of establishing synergistic or collaborative relations between both types of molecules [ 100 ]. The authors speculated that the carbosilane dendrimer structures, already known for their on contact antibacterial potency against Gram-positive and Gram-negative bacteria strains and for their poor tendency to induce resistances probably due to their easier penetration into the phospholipid bilayer could help to protect or transport AMPs inside bacterial membranes [ 100 ]. The antibacterial activity of ammonium-terminated carbosilane Ds (namely 3 and 4) was assessed against E. coli and S. aureus strains and was compared to that of the four nanocomposites [namely 11, 14 (covalent nanoconjugates) and 15, 16 (non-covalent nanoconjugates)] obtained.…”

“…The MIC values calculated for both groups of compounds were comparable in the case of E. coli , but not in the case of S. aureus , since the nanocomposites (11, 15) displayed a significantly higher antibacterial activity than that of corresponding dendrons (3) (MIC values of 32 and 64 μg/mL vs. 128 μg/mL, respectively). This trend also applied to the nanocomposite (16), when compared to the corresponding dendron (4) (MIC value of 4 μg/mL vs. 8 μg/mL) ( Table 9 ) [ 100 ].…”

Synthesis and Antimicrobial Properties of a Ciprofloxacin and PAMAM-dendrimer Conjugate

“…There have also been in vitro studies on the effect of co-administering antibiotics with poly(propylene imine) dendrimers showing similar results [20]. Antimicrobial dendrimers are also known and some examples are the quaternary silicon-dendrimers pioneered by de la Mata, Gomez and coworkers [21][22][23][24] the small peptide-dendrons by Urbanczyk-Lipkowska and coworkers [25-28] and the peptide dendrimers by Reymond and coworkers [29][30][31][32].Covalent conjugates between antibiotics have been described by Kannan and coworkers [33], who synthesized a covalent conjugate between Azithromycin and a hydroxyl-terminated generation 4 PAMAM-dendrimer that released the antibiotic after cellular uptake enabling treatment of intracellular C. trachomatis in vitro. Baker and coworkers [34] described a photocleavable conjugate between a dendrimer and Ciprofloxacin that released the drug upon illumination.In the present work, we wanted to investigate if a dendrimer-antibiotic conjugate could have antimicrobial activity in itself and not just be an advanced and expensive drug-delivery system.…”

“…There have also been in vitro studies on the effect of co-administering antibiotics with poly(propylene imine) dendrimers showing similar results [20]. Antimicrobial dendrimers are also known and some examples are the quaternary silicon-dendrimers pioneered by de la Mata, Gomez and coworkers [21][22][23][24] the small peptide-dendrons by Urbanczyk-Lipkowska and coworkers [25-28] and the peptide dendrimers by Reymond and coworkers [29][30][31][32].…”

pH-Sensitive Dendrimersomes of Hybrid Triazine-Carbosilane Dendritic Amphiphiles-Smart Vehicles for Drug Delivery

“…Dendritic molecules, dendrimers and dendrons, are versatile platforms to design supramolecular nanoconstructions for robust drug delivery [ 4 , 5 , 6 , 7 , 8 ]. In particular, carbosilane dendrimers are efficient tools for antibacterial [ 9 ] and antiviral therapy [ 10 ], nucleic acid delivery [ 11 ], cancer treatment [ 12 ], imaging [ 13 ], functional nanomaterials [ 14 , 15 ], and so on. It should be noted that dendritic architectures give room to design various types of supramolecular constructions based on the molecular topology of building blocks.…”