Every year, 700,000 people die from antibiotic resistance. A growing global population is unfortunately generating growing resistance to established antibiotic treatments – a threat that has been met with insufficient funding and dwindling inspiration as commercial incentives for the development of new antibiotics have plummeted. A new study by researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health System, addresses this growing problem in antibiotic development by using a new interdisciplinary approach to build a robust antibiotic library, generated by a computer program and to identify an effective antibiotic for targeted use in a bone cement matrix. This approach could potentially be used to treat bone infections, a common complication after orthopedic surgeries. Their results are published in Nature Biomedical Engineering.
“Currently, the Food and Drug Administration (FDA) has only approved bone cements loaded with antibiotics not originally developed for bone tissue,” said Hae Lin Jang, PhD, co-director of Brigham’s Center for Engineered Therapeutics. and principal investigator of the laboratory. for the development of advanced biomaterials and biotechnologies. “In addition to not being specific to bone tissue, resistance has emerged against these antibiotics. We need to create a new generation of antibiotics optimized to meet this emerging need. »
This growing fight against antibiotic resistance has merged with an equally growing aging population, which now requires more orthopedic procedures than ever before. Common procedures such as knee and hip replacements can lead to bacterial infection, such as Staphylococcique, who is currently being treated with systemic antibiotics. Systemic exposure to antibiotics does not specifically target the infection; therefore, huge doses are required, leading to the unintended consequences of drug resistance and destruction of beneficial microbiota. To address this growing problem, collaborating researchers from Brigham’s Department of Medicine and Department of Orthopedic Surgery sought to create a potent, locally delivered combination of antibiotic and bone cement.
To design a new antibiotic for specific local delivery via a bone cement matrix, polymethyl methacrylate (PMMA) bone cement was used – the gold standard accepted by the FDA. The team pre-screened molecules for antibiotic design and screened drug-susceptible and drug-resistant bacteria in a preclinical model. Finally, the team compared the clinically used PMMA bone cement and the new antibiotic-loaded PMMA bone cement using prophylactic treatment and established treatment. Staphylococcique– model of infected tibial lesion.
The researchers identified the dual action antibiotic VCD-077, studying its activity and efficacy in cells and in animal models. VCD-077 not only exhibited the desired drug release kinetics without affecting the stability of PMMA bone cement, but also demonstrated high efficacy against a wide range of drug-resistant bacterial strands and slowed the development of a future resistance. In fact, VCD-077-loaded PMMA bone cement has shown greater efficacy than any antibiotic-loaded bone cement currently used against Staphylococcique bone infections in a rat model.
Before clinical application, the team must deal with two major constraints: the potential differences between the rat model studied and humans, and the necessary toxicity studies. But, the researchers note, the future is bright for tissue-specific localized treatment, such as a minimally invasive injection of antibiotic-infused bone cement. Focusing on tissue specificity early in development and the interaction between drug and device can help design treatments that work precisely without perpetuating drug resistance. Additionally, the team’s new application of computer engineering to finding molecules and optimizing antibiotic design has been a huge success, suggesting potential for computer programming and AI technology to streamline development. of drugs.
“The future lies in blending artificial intelligence and drug discovery to make the development of new antibiotics more efficient and cost-effective than ever before,” said co-corresponding author Shiladitya Sengupta, PhD, co-director of the Brigham’s Center for Engineered Therapeutics. “The interdisciplinarity in our approach and the specificity of our drug development will truly bring about a new paradigm in medical engineering. »
Says Jang, “Treatment can get more complicated, and bacteria can get more sophisticated, but we biomedical engineers are also getting more sophisticated. »
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Materials provided by Brigham and Women’s Hospital. Note: Content may be edited for style and length.