New technology can revive bactericidal effects of conventional antibiotics in E. coli MDR infections

A research team led by Professor Kelvin Yeung Wai-kwok of the Department of Orthopedics and Traumatology, Faculty of Clinical Medicine, LKS School of Medicine, Hong Kong University (HKUMed) has designed a non-invasive technology to revitalize bactericidal anti-bacterial antidote. ) Escherichia coli (E. coli)-related deep tissue infections, such as urinary tract and peritoneal infections.

The study found that the bacterium MDR E. coli is again sensitive to the intervention of conventional antibiotics when the bacterium is exposed to a mild hyperthermic condition (approximately 50 degrees Celsius). Therefore, the HKUMed team is designing a new microwave-responsive microsphere encapsulated with conventional antibiotics that can deliver in situ hyperthermic therapy and antibiotic treatment simultaneously. The result is published in Advanced functional materials.

Background

Among all MDR bacteria, MDR E. coli, defined as Gram-negative bacteria, is one of the three dangerous pathogens with critical priority identified by the World Health Organization (WHO). Due to its unique outer membrane (OM) structure, the bacterium can be immunized against the treatment of most antibiotics available in clinics.

In short, there is a specific barrier found in the structure, namely a β-tube assembly machine (BAM complex). When this complex is combined with two other barriers MDR efflux pump and enzymatic degradation in the cytoplasm, the bacterium can effectively block the attack of antibiotics. However, conventional treatment can only weaken the function of the BamA protein (a major component of the BAM complex) instead of all three barriers simultaneously.

Research method and findings

The HKUMed research team first found that these barriers would be temporarily paralyzed if the temperature at the site of infection rose to about 50 degrees Celsius in just 10 minutes, making this short and mild thermal treatment tolerable by human tissues.

When conventional antibiotics can be used at the same time, the team believes that infection caused by gram-negative bacteria can be completely eliminated. Therefore, they are designing a new microwave-responsive microsphere consisting of an FDA-approved biopolymer called poly (lactic-co-glycolic acid) (PLGA), which can generate light heat subjected to microwave stimulation.

When this in-situ microwave hyperthermal (MWH) strategy is applied, it can effectively sensitize E. coli MDR to conventional antibiotic treatments such as β-lactam, aminoglycoside, and tetracycline antibiotics.

The results show that MWH causes structural turbulence of the BAM complex, functional obstruction of MDR efflux pumps, and catalytic paralysis of related hydrolytic or modifying enzymes. Also, the efficacy of treatment of this collective antibacterial strategy has been demonstrated in animal models with urinary tract infection and peritoneal infection.

Research significance

We are inspired by the mechanism of fever in the human body when a person fights a bacterial infection. We then found that heat could help compromise the barriers constructed by E. coli MDR. When MWH is combined with the use of commercially available antibiotics, this approach can significantly reduce the severity of gram-negative bacterial infection (eg, MDR E. coli) in deep tissues. We may also consider encapsulating antitumor drugs along with antibiotics to treat bone cancer patients with bacterial infection after surgery in future practice.

Kelvin Yeung Wai-kwok, Professor, Department of Orthopedics and Traumatology, Faculty of Clinical Medicine, LKS School of Medicine, Hong Kong University

Source:

The University of Hong Kong

Reference in the magazine:

Mao, S., et al. (2022) Reversing Multi-Resistant E. coli by compromising its BAM biogenesis and enzymatic catalysis by microwave hyperthermic therapy. Advanced functional materials. doi.org/10.1002/adfm.202202887

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