Antimicrobial Organometallic Dendrimers with Tunable Activity against Multidrug-Resistant Bacteria

Abstract

Multidrug-resistant pathogens are an increasing threat to public health. In an effort to curb the virulence of these pathogens, new antimicrobial agents are sought. Here we report a new class of antimicrobial organometallic dendrimers with tunable activity against multidrug-resistant Gram-positive bacteria that included methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Mechanistically, these redox-active, cationic organometallic dendrimers induced oxidative stress on bacteria and also disrupted the microbial cell membrane. The minimum inhibitory concentrations, which provide a quantitative measure of the antimicrobial activity of these dendrimers, were in the low micromolar range. AlamarBlue cell viability assay also confirms the antimicrobial activity of these dendrimers. Interestingly, these dendrimers were noncytotoxic to epidermal cell lines and to mammalian red blood cells, making them potential antimicrobial platforms for topical applications.

Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO)

“…), and inducing oxidative stress. 71,89 In general, the mechanisms of bactericidal surfaces are: 1) contact-based bactericidal activity (e.g., QAC, etc.) which affects the ion-exchange processes and cause general perturbations that destabilize the cytoplasmic membranes of bacteria, resulting in leakage of the intracellular fluid; and 2) release-based bactericidal (e.g., metal ions, antibiotics, etc.…”

“…To improve the NO payload and stability, achieve targeted NO delivery through multi-functionalization and elongate NO releasing lifetime, many different scaffolds have been used as NO-releasing or NO-generating vehicles. These include micelles, 138,190,191 microbubbles, 192 proteins, 193–197 liposomes, 126,198 inorganic nanoparticles (such as silica, 70,199–203 gold, 204,205 microparticles, 198,206 zeolites, 207,208 ), metal-organic frameworks (MOFs), 209–212 dendrimers, 71,213,214 xerogels, 215–217 electrospun fibers, 88,100,218 natural polymers (chitosan, 85–87,219–221 gelatin, 222 etc. ), and other organic polymers (polymethacrylate, 223 polyester, 224,225 polydimethylsiloxane (PDMS), 226 polysaccharides, 227,228 hydrogel, 178,179,229,230 PVA, 49,231,232 polyurethanes, 161,162,233,234 and PVC 154 ).…”

Quaternized and Thiazole‐Functionalized Free Radical‐Generating Organometallic Dendrimers as Antimicrobial Platform against Multidrug‐Resistant Microorganisms

“…The constituent bioactive moieties of our target hybrid antimicrobial macromolecules include a ferrocenyl derivative, cationic η 6 ‐dichlorobenzene‐η 5 ‐cyclopentadienyliron(II) complex, and quaternary ammonium groups or an antimicrobial thiazole, 2‐mercaptobenzothiazole. The complex, as well as its dendrimer and polymer derivatives, were proved in our previous studies to exhibit antimicrobial activity via mechanisms that include disruption of the bacterial cell membrane and induction of oxidative stress on microorganisms . Also, previously, it was shown that the activity of the dendrimer derivatives is highly dependent on dendrimer generation with bulkier, higher generation dendrimers being less active and in some cases, inactive .…”

“…The complex, as well as its dendrimer and polymer derivatives, were proved in our previous studies to exhibit antimicrobial activity via mechanisms that include disruption of the bacterial cell membrane and induction of oxidative stress on microorganisms . Also, previously, it was shown that the activity of the dendrimer derivatives is highly dependent on dendrimer generation with bulkier, higher generation dendrimers being less active and in some cases, inactive . This finding as well as the increasing interest in antimicrobial high molecular weight macromolecules, motivated us to design our target hybrid antimicrobial high molecular weight dendrimers by integrating the activity of cationic η 6 ‐dichlorobenzene‐η 5 ‐cyclopentadienyliron(II) complex with that of quaternary ammonium groups or 2‐mercaptobenzothiazole into one system.…”

Metal-containing and related polymers for biomedical applications

“…16). 129 These antimicrobial organometallic dendrimers showed tunable activity against multidrug-resistant Gram-positive bacteria, such as MRSA and vancomycin-resistant Enterococcus faecium , with the minimum inhibitory concentration (MIC) in the low micromolar range. Interestingly, these dendrimers were non-cytotoxic to epidermal cell lines and to mammalian red blood cells.…”