Newly developed Janus nanoparticles restore antibiotic efficacy — Expected to help solve drug-resistant bacteria problem

Specially Appointed Associate Professor (full-time) Martijn Zwama and Professor Kunihiko Nishino from SANKEN (the Institute of Scientific and Industrial Research), along with Graduate Student Nozomi Sakurai of the School of Pharmaceutical Sciences at the University of Osaka, Professor Yan Yu from Washington University in St. Louis, Swagata Bhattacharyya from Indiana University Bloomington, and their colleagues have succeeded in restoring antibiotic susceptibility in multidrug-resistant Gram-negative bacteria using newly developed amphiphilic Janus nanoparticles. This achievement is expected to provide a breakthrough in solving the global challenge of drug-resistant bacteria. The research was published in Nano Letters.

The number of infections caused by drug-resistant bacteria is increasing around the world. Gram-negative bacteria such as Acinetobacter baumannii and Escherichia coli possess robust outer membranes and multidrug efflux systems, which makes them difficult to treat with drugs and therefore an extremely serious threat. Many of these bacteria are already resistant to multiple antibiotics, and some strains have acquired resistance to nearly all drugs currently used for treatment. Resistance arises from mutations in antibiotic targets, degradation or modification of antibiotics, changes in membrane permeability, and overexpression of efflux pumps that actively expel drugs from cells. As a result, the effectiveness of commonly used antibiotics is rapidly being lost.

The development of new adjuvant compounds that can be used in combination with antibiotics to restore bactericidal effects against resistant bacteria is an urgent challenge if we are to maintain the utility of existing antibiotics.

The research team developed Janus nanoparticles, which have a unique bifacial (amphiphilic) structure composed of a hydrophobic hemisphere and a multivalent cationic hemisphere. These particles are designed to interact with bacterial membranes, weaken their structure, and enhance the activity of multiple classes of antibiotics.

Janus nanoparticles adhere to the cell membranes of Gram-negative bacteria, deform the membrane structure, and enhance the uptake and activity of co-administered antibiotics. At very low concentrations, the nanoparticles alone do not kill bacteria, but they work synergistically when combined with antibiotics.

Strong synergistic effects were confirmed between Janus nanoparticles and multiple antibiotics including erythromycin, novobiocin, rifampicin, kanamycin, ethidium bromide, and cloxacillin. The required antibiotic concentration was reduced by more than 100-fold across multiple bacterial species, dependent on the type of antibiotic. Furthermore, since symmetrical nanoparticles showed no synergistic effect, the asymmetry was found to be essential for their function.

The team also developed a new system embedded in agar gel, which can reliably come into contact with motile bacteria such as E. coli and consistently enhance the effects of slow-acting antibiotics such as β-lactams. This demonstrates potential clinical applications, including antibacterial coatings and wound dressing materials.

This research demonstrates a new materials chemistry-based antibiotic activation strategy that does not rely on genetic or biochemical targeting. Because Janus nanoparticles act through physical interactions with bacterial membranes, the bacteria are unlikely to develop resistance, and the nanoparticles can exhibit synergistic effects with many existing antibiotics. When used in combination as an adjuvant, they extend the effective lifespan of existing drugs. Furthermore, agar gels embedded with nanoparticles are expected to enable new clinical applications such as antibacterial coatings and drug delivery systems to control multidrug-resistant bacterial infections.

Nishino commented: "This research demonstrates new concepts that could not have been achieved within a single discipline through an international collaboration combining materials chemistry and microbiology. Multidrug-resistant bacterial infections are becoming increasingly severe on a global scale and pose a major problem in clinical settings. The amphiphilic Janus-type nanoparticles demonstrated in this study represent a new strategy for restoring the effectiveness of existing antibiotics, and I believe this is a technology with significant societal impact, particularly because the development of resistance is unlikely to occur. I hope the results of this research will contribute to future measures against drug-resistant bacteria."

Journal Information
Publication: Nano Letters
Title: Amphiphilic Janus Nanoparticles Synergize with Antibiotics to Restore Susceptibility in Drug-Resistant Gram-Negative Bacteria
DOI: 10.1021/acs.nanolett.5c05337