Abstract
Because of the emergence of antimicrobial resistance to traditional small-molecule drugs, cationic antimicrobial polymers are appealing targets. Mycobacterium tuberculosis is a particular problem, with multi- and total drug resistance spreading and more than a billion latent infections globally. This study reports nanoparticles bearing variable densities of poly(dimethylaminoethyl methacrylate) and the unexpected and distinct mechanisms of action this multivalent presentation imparts against Escherichia coli versus Mycobacterium smegmatis (model of M. tuberculosis), leading to killing or growth inhibition, respectively. A convergent “grafting to” synthetic strategy was used to assemble a 50-member nanoparticle library, and using a high-throughput screen identified that only the smallest (2 nm) particles were stable in both saline and complex cell media. Compared with the linear polymers, the nanoparticles displayed two- and eight-fold enhancements in antimicrobial activity against M. smegmatis and E. coli, respectively. Mechanistic studies demonstrated that the antimicrobial particles were bactericidal against E. coli due to rapid disruption of the cell membranes. Conversely, against M. smegmatis the particles did not lyse the cell membrane but rather had a bacteriostatic effect. These results demonstrate that to develop new polymeric antituberculars the widely assumed, broad spectrum, membrane-disrupting mechanism of polycations must be re-evaluated. It is clear that synthetic nanomaterials can engage in more complex interactions with mycobacteria, which we hypothesize is due to the unique cell envelope at the surface of these bacteria.
Highlights
Infectious diseases are the second-leading cause of death worldwide and the third-leading cause of death in economically advanced countries.[1]
Four different degrees of polymerization (DP) were targeted for each monomer, DP10, DP25, DP50, and DP100, to provide a range of molecular weights to screen for stability and activity
The produced polymers were characterized by 1H NMR and size exclusion chromatography (SEC)
Summary
Infectious diseases are the second-leading cause of death worldwide and the third-leading cause of death in economically advanced countries.[1]. Feldheim et al.[32] showed that ∼2 nm particles with specific mixtures of 4-mercaptobenzoic acid, cysteamine, 3-mercapto-1-propanesulfonic acid, and 2-diethylaminoethanethiol on their surface showed increased activity against M. smegmatis over E. coli None of these particles lead to significant membrane disruption, though, implying that nonlytic mechanisms are an untapped route to modulate bacteria growth and infection with cationic polymers. Disrupting this is likely to require design rules very different from, for example, E. coli Considering the above, this manuscript reports a detailed study into the use of “multicopy” multivalent nanoparticles and their antimicrobial activity against mycobacteria and a Gram-negative strain. Minimum bactericidal concentration (MBC) of the particles were determined against M. smegmatis and E. coli. For hemagglutination determination 25 μL of this mixture was added to 75 μL of PBS in a U-bottom 96-well plate and incubated for a further hour at room temperature. The absorbance was measured at 450 nm and compared against deionized water as a positive control for lysis and PBS as a negative control to determine % hemolysis
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