Multivalent Antimicrobial Polymer Nanoparticles Target Mycobacteria and Gram-Negative Bacteria by Distinct Mechanisms

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.

Nano-vehicles give new lease of life to existing antimicrobials

“…For example, polyion complex (PIC) nanoparticles carrying the last resort antimicrobial polymyxin B (Pol-B) had a sustained inhibitory effect on the growth of P. aeruginosa [52]. Similarly, polymer nanoparticles decorated with different densities of poly(dimethylaminoethyl methacrylate) have antimicrobial activity against E. coli and Mycobacterium smegmatis [53]. Interestingly, the mechanism of action against the two bacterial strains differedthe nanoparticles were bactericidal against E. coli and bacteriostatic against M. smegmatis.…”

Photochemical “In‐Air” Combinatorial Discovery of Antimicrobial Co‐polymers

“…2‐(Dimethylamino)ethyl methacrylate (DMAEMA) was chosen as the cationic component based on our previous work showing it has potent anti‐mycobacterial activity. Herein, there did not appear to be a molecular‐weight effect of the DPs tested (between 10 and 100) therefore DP 75 was chosen . Figure B and Table show results of three parallel DMAEMA polymerizations in 96‐well plates targeting degrees of polymerization of 25, 50, and 100.…”

“…Escherichia coli and Mycobacteria smegmatis were used to represent Gram negative and Mycobacteria (which includes M. tuberculosis ). The MIC 99 (minimum concentration to stop growth of 99 % of organisms) of homo‐PDMAEMA is 250 and 31.3 μg mL −1 against E. coli and M. smegmatis , respectively . Co‐polymers were added to the bacteria at 0.5×MIC 99 of PDMAEMA to enable selection of co‐polymers that were at least two‐fold more active.…”

The Effects of Luminescent CdSe Quantum Dot-Functionalized Antimicrobial Peptides Nanoparticles on Antibacterial Activity and Molecular Mechanism

“… 11 The amino acid sequence and structure of different AP are obviously different, but they all have an amphipathic structure and can be combined with other compounds. 12 , 13 Therefore, they can easily interact with the negatively charged components on the bacterial cell membrane and integrate into the lipid bilayer. However, their poor biocompatibility is one of the main obstacles to the clinical development of a large number of common AP.…”