Polymer conjugates that adapt vancomycin to overcome resistance in Gram-negative bacteria

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Non-technical abstractThe rapid spread of drug-resistant bacteria is a severe global health crisis. In the last 40 years, there has not been new antibiotics to treat drug-resistant bacterial infections. One issue for creating a new antibiotic therapy is the impermeable outer membrane (OM) of Gram-negative bacteria such as Escherichia coli, which prevents entry of certain antibiotics. For example, vancomycin is a promising antibiotic of last resort, but since it cannot penetrate the bacteria’s OM, it is not successful for Gram-negative bacterial infections. The long-term goal of this study is to develop a new way to convert vancomycin into an effective treatment of drug-resistant Gram-negative bacterial infections. The information from this study will help researchers create new rules to design a carrier that helps effective drugs bypass the OM and reach the target sites within bacteria. The study increases the number of antibiotics available to treat drug-resistant bacterial infections and significantly improve a patient’s health. The proposed research is interdisciplinary. Students and postdocs will learn molecular design, how to build polymer-antibiotic pairs, and conduct research projects involving polymer chemistry, biomaterials, and microbiology. To contribute to diversity, equity, and inclusion, the PI accepts students from the University of Michigan’s Undergraduate Research Opportunity Program. The PI engages primary and secondary schools through the ACS POLY/PMSE student chapter outreach program. The PI participates in the UM’s Summer Research Opportunity Program as a research mentor for under-represented students from across the country. The PI will also build international research collaborations and student exchange programs with research groups in Japan. Technical abstractConverting Gram-positive-only vancomycin to be active against Gram-negative bacteria is a promising approach to increase our arsenal of new antibiotics against drug-resistant bacteria. However, molecular rules for the conversion have not been established for the large/globular glycopeptide vancomycin. To that end, membrane-active polymer carriers will be designed to pass through the outer membrane (OM), increase the local concentration of vancomycin on the inner (cytoplasmic) membrane (IM), and deliver vancomycin to the cell division septum region, where vancomycin would be most active. The specific goals of this study are to understand the structure-activity-mechanism relationship of the polymer-drug conjugates and determine their therapeutic potential for clinical applications. To achieve these goals, covalent conjugates of vancomycin with the cationic amphiphilic copolymers will be synthesized through click chemistry. The antimicrobial activity and underlying mechanism of action will be studied to determine the abilities of conjugates to permeate the OM, concentrate vancomycin on the IM, and accumulate at the septum. To evaluate the therapeutic potential of conjugates, the PI will evaluate the cytotoxicity of conjugates to mammalian cells, potency against carbapenem-resistant E. coli, and the spectrum of activity against other Gram-negative bacterial pathogens. The expected outcomes will lead to a rational and predictable guideline for molecular design of polymer carriers for targeted drug delivery to the specific membrane structure within bacteria. The outcomes of this research will also increase our understating of the physicochemical interactions between polymer and bacterial cell structures, which can be exploited to enhance the antimicrobial activity of antibiotics.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.