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Supramolecular cationic assemblies against multidrug-resistant microorganisms: activity and mechanism of action.

ABSTRACT: The growing challenge of antimicrobial resistance to antibiotics requires novel synthetic drugs or new formulations for old drugs. Here, cationic nanostructured particles (NPs) self-assembled from cationic bilayer fragments and polyelectrolytes are tested against four multidrug-resistant (MDR) strains of clinical importance. The non-hemolytic poly(diallyldimethylammonium) chloride (PDDA) polymer as the outer NP layer shows a remarkable activity against these organisms. The mechanism of cell death involves bacterial membrane lysis as determined from the leakage of inner phosphorylated compounds and possibly disassembly of the NP with the appearance of multilayered fibers made of the NP components and the biopolymers withdrawn from the cell wall. The NPs display broad-spectrum activity against MDR microorganisms, including Gram-negative and Gram-positive bacteria and yeast.

SUBMITTER: Carrasco LD

PROVIDER: S-EPMC4394535 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Supramolecular cationic assemblies against multidrug-resistant microorganisms: activity and mechanism of action.

Carrasco Letícia Dias de Melo LD Sampaio Jorge Luiz Mello JL Carmona-Ribeiro Ana Maria AM

International journal of molecular sciences 20150319 3

The growing challenge of antimicrobial resistance to antibiotics requires novel synthetic drugs or new formulations for old drugs. Here, cationic nanostructured particles (NPs) self-assembled from cationic bilayer fragments and polyelectrolytes are tested against four multidrug-resistant (MDR) strains of clinical importance. The non-hemolytic poly(diallyldimethylammonium) chloride (PDDA) polymer as the outer NP layer shows a remarkable activity against these organisms. The mechanism of cell deat ...[more]

PMID: 25809608

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Project description:The increasing emergence of antibiotic resistance is an urgent threat to global health care; thus, there is a need for new therapeutics. Guanidine is the preferred functional group for antimicrobial design and development. Herein, the potential antibacterial activity of the guanidine derivative isopropoxy benzene guanidine (IBG) against multidrug-resistant (MDR) bacteria was discovered. The synergistic antibacterial activity of IBG and colistin was determined by checkerboard assay, time-killing curve, and mouse experiments. The antibacterial mechanism of IBG was verified in fluorescent probe experiments, intracellular oxidative phosphorylation assays, and transcriptome analysis. The results showed that IBG displays efficient antibacterial activity against Gram-positive pathogens and Gram-negative pathogens with permeabilized outer membranes. Further mechanistic studies showed that IBG triggers cytoplasmic membrane damage by binding to phosphatidylglycerol and cardiolipin, leading to the dissipation of proton motive force and accumulation of intracellular ATP. IBG combined with low levels of colistin enhances bacterial outer membrane permeability and increases the accumulation of reactive oxygen species, as further evidenced by transcriptome analysis. Furthermore, the efficacy of IBG with colistin against MDR Escherichia coli in three infection models was demonstrated. Together, these results suggest that IBG is a promising adjuvant of colistin, providing an alternative approach to address the prevalent infections caused by MDR Gram-negative pathogens. IMPORTANCE As antibiotic discovery stagnates, the world is facing a growing menace from the emergence of bacteria that are resistant to almost all available antibiotics. The key to winning this race is to explore distinctive mechanisms of antibiotics. Thus, novel efficient antibacterial agents and alternative strategies are urgently required to fill the void in antibiotic development. Compared with the large amount of money and time required to develop new agents, the antibiotic adjuvant strategy is a promising approach to inhibit bacterial resistance and increase killing of bacteria. In this study, we found that the guanidine derivatives IBG not only displayed efficient antibacterial activities against Gram-positive bacteria but also restored colistin susceptibility of Gram-negative pathogens as an antibiotic adjuvant. More in-depth study showed that IBG is a potential lead to overcome antibiotic resistance, providing new insight into future antibiotic discovery and development.

Project description:The overuse of antibiotics exacerbates the development of antibiotic-resistant bacteria, threatening global public health, while most traditional antibiotics act on specific targets and sterilize through chemical modes. Therefore, it is a desperate need to design novel therapeutics or extraordinary strategies to overcome resistant bacteria. Herein, we report a positively charged nanocomposite PNs-Cur with a hydrodynamic diameter of 289.6 nm, which was fabricated by ring-opening polymerization of ε-caprolactone and Z-Lys-N-carboxyanhydrides (NCAs), and then natural curcumin was loaded onto the PCL core of PNs with a nanostructure through self-assembly, identified through UV-vis, and characterized by scanning electron microscopy (SEM) and dynamic light scattering (DLS). Especially, the self-assembly dynamics of PNs was simulated through molecular modeling to confirm the formation of a core-shell nanostructure. Biological assays revealed that PNs-Cur possessed broad-spectrum and efficient antibacterial activities against both Gram-positive and Gram-negative bacteria, including drug-resistant clinical bacteria and fungus, with MIC values in the range of 8-32 μg/mL. Also, in vivo evaluation showed that PNs-Cur exhibited strong antibacterial activities in infected mice. Importantly, the nanocomposite did not indeed induce the emergence of drug-resistant bacterial strains even after 21 passages, especially showing low toxicity regardless of in vivo or in vitro. The study of the antibacterial mechanism indicated that PNs-Cur could indeed destruct membrane potential, change the membrane potential, and cause the leakage of the cytoplasm. Concurrently, the released curcumin further plays a bactericidal role, eventually leading to bacterial irreversible apoptosis. This unique bacterial mode that PNs-Cur possesses may be the reason why it is not easy to make the bacteria susceptible to easily produce drug resistance. Overall, the constructed PNs-Cur is a promising antibacterial material, which provides a novel strategy to develop efficient antibacterial materials and combat increasingly prevalent bacterial infections.

Dataset Information

Supramolecular cationic assemblies against multidrug-resistant microorganisms: activity and mechanism of action.

Publications

Supramolecular cationic assemblies against multidrug-resistant microorganisms: activity and mechanism of action.

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