Novel combination therapy developed for treating VRE


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Researchers from Antimicrobial resistance (AMR) Interdisciplinary Research Group (IRG) in Singapore-MIT Research and Technology Alliance (SMART), a research project of the Massachusetts Institute of Technology in Singapore, in collaboration with the Singapore Center for Environmental Life Science Engineering (SCELSE), Nanyang Technological University (NTU), MIT, and the University of Geneva, developed a novel combination therapy using an antifungal agent. For cancer, mitoxantrone (MTX), combined with an antibiotic, vancomycin, to treat bacteria that are resistant to vancomycin, which is also known as vancomycin-resistant Enterococcus faecalis (VRE). The treatment uniquely targets both the VRE and the host, stimulating the host immune system to more effectively clear the bacterial infection and speed up the healing of infected wounds.

VRE/CDC image

Antimicrobial resistance is a major global health concern 4.95 million deaths due to infections associated with or attributable to antimicrobial resistance In 2019 alone. By 2050, it will The Asia-Pacific region is expected to account for 47% of AMR-related deaths worldwide. If immediate and coordinated action is not taken to avert a possible drug resistance crisis. In response to this growing health threat, new and innovative approaches to treat bacterial infections are being developed, including the use of antimicrobials that can overcome resistance mechanisms and host-directed therapies that enhance the human innate immune system to combat bacterial infections.

VRE is a bacteria that is difficult to kill due to its increasing resistance to antibiotics and can cause serious infections, including urinary tract, bloodstream, and wound infections associated with catheters or surgical procedures. Treating VRE infections has posed a significant challenge as the bacteria have shown resistance to vancomycin – an antibiotic commonly used to treat endocarditis, skin, stomach and enteritis caused by Gram-positive bacteria – and other commonly used antibiotics.

In this research, the team tested the efficacy of MTX and antibiotic activity against VRE, both of which are antibiotics in the laboratory And in vivo. Despite the resistance of the VRE to vancomycin, MTX was found to inhibit VRE growth more effectively when used in the presence of vancomycin. This result is due to the synergistic relationship between MTX and vancomycin, which renders the VRE more sensitive to vancomycin by lowering the concentration of vancomycin required to kill the VRE. The research has also shown that MTX improves wound healing by enhancing the ability of macrophages — a type of white blood cell that kills microorganisms, removes dead cells, and triggers the action of other immune cells — to fight off VRE infection and recruit more immune cells to the site of infection.

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In a paper titled Mitoxantrone targets both host and bacteria to overcome vancomycin resistance in Enterococcus faecalis.Publication in the scientific journal Science advancesThe research showed that MTX, which is commonly used to treat acute leukemia, prostate and breast cancer, as well as multiple sclerosis, is a potent antibiotic against VRE. It acts synergistically with vancomycin, enhances macrophage recruitment and bactericidal activity, and has great potential as a dual antibacterial and host therapy to overcome VRE.

“To address the global health threat of antimicrobial resistance, it is imperative to find innovative and effective solutions to combat bacterial infections. Through our research, we have discovered the effective combination of MTX and vancomycin, which is highly effective in inhibiting the growth of VRE. Moreover, it also possesses the ability to promote the host’s immune system and improving wound healing by bringing more immune cells to the site of infection and by making immune cells better at killing bacteria,” says the paper, principal investigator of SMART AMR, and professor of biology in the Koch Institute for Integrative Cancer Research at MIT.

“Treatment options for VRE infections are very limited due to their endogenous and acquired resistance to many conventional antibiotics, including vancomycin,” said Dr. Ronnie da Silva, first author of the paper and a postdoctoral researcher at SMART AMR.

The researchers are continuing their research with more preclinical studies to prepare for a clinical trial, specifically aimed at developing topical treatments for chronic diabetic wound infections. Dr. Kimberly Klein, co-author of the paper, Principal Investigator of SMART AMR, and Professor at the University of Geneva, added, “Our research lays an important foundation for exploring the potential impact of using mitoxantrone to treat bacterial infections. As we continue to explore the full range of applications with further research, we aim to Creating transformative change using innovative new therapies to overcome vancomycin resistance in the future.”

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