700,000 people die each year from antibiotic resistance. A growing world population sadly generates increasing resistance to established antibiotic treatments, a threat that has been met with insufficient funding and dwindling inspiration as commercial incentives to develop new antibiotics have declined. 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 library of antibiotics 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 surgical procedures. Their findings are published in Biomedical engineering of nature.
“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, resistance against these antibiotics has emerged. We need to create a new generation of antibiotics optimized to meet this emerging need.”
This growing struggle with antibiotic resistance has merged with a similarly growing aging population, which now requires more orthopedic procedures than ever. Common procedures like knee and hip replacements can cause bacterial infections, for example staph, currently treated with systemic antibiotics. Systemic exposure to antibiotics does not precisely target infection; therefore, huge doses are needed, resulting in the unintended consequences of drug resistance and destruction of the beneficial microbiota. To remedy this growing problem, collaborative researchers from Brigham’s Department of Medicine and Orthopedic Surgery aimed to create a potent combination of antibiotic and bone cement delivered locally.
To design a new antibiotic for specific local administration via a bone cement matrix, bone cement made of polymethyl methacrylate (PMMA), the gold standard accepted by the FDA, was used. The team selected molecules for antibiotic design and examined drug-sensitive and drug-resistant bacteria in a preclinical model. Finally, the team compared clinically used PMMA bone cement and new antibiotic-loaded PMMA bone cement using prophylaxis and a staph– Infected tibial lesion model.
Researchers identified the double-acting antibiotic VCD-077, studying its activity and efficacy in cells and animal models. VCD-077 not only showed the desired drug release kinetics without affecting the stability of the PMMA bone cement, but also demonstrated high efficacy against a wide range of drug-resistant bacterial filaments and slowed the development of resistance. future. In fact, PMMA bone cement loaded with VCD-077 showed greater efficacy than all antibiotic loaded bone cements currently used against staph bone infections in a rat model.
Prior to clinical application, the team faces two major limitations: potential differences between the rat model studied and humans, and the toxicity studies required. 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 from the development stage and drug-device interaction can help design treatments that work precisely without perpetuating drug resistance. Additionally, the team’s new application of computer engineering to find molecules and optimize antibiotic design has been hugely successful, suggesting the potential for computer programming and artificial intelligence technology to simplify drug development.
“The future lies in mixing artificial intelligence and drug discovery to make the development of new antibiotics more efficient and cost-effective than ever,” said co-author Shiladitya Sengupta, PhD, co-director of Brigham’s Center for Engineered Therapeutics. “The interdisciplinarity in our approach and the specificity in our drug development will truly lead to a new paradigm of medical engineering.”
Jang said: “Treatment may become more complicated and bacteria may become more sophisticated, but we biomedical engineers are also becoming more sophisticated.”
Materials provided by Brigham and Women’s Hospital. Note: The content can be changed by style and length.