Antibiotic-resistant Enterobacteriaceae, including carbapenem-resistant and extended spectrum ?-lactamase producing Klebsiella spp., Escherichia coli, and Enterobacter spp. are considered by the Centers for Disease Control and Prevention (CDC) to be urgent and serious health threats to the United States. Our long term goal is to develop and evaluate novel antibiotics for the Enterobacteriaceae. We will attain our goal with polyacrylate co-polymers further grafted with siderophore mimics. Siderophores are powerful iron chelators synthesized and excreted by microorganisms to sequester and return the iron needed for their growth. All Enterobacteriaceae rely primarily on two siderophores for their iron acquisition: enterobactin and aerobactin. Because iron is a limiting factor in bacterial growth in the human body (including on skin and in blood, urine and cerebrospinal fluid), these two siderophores are long-established as virulence factors for all Enterobacteriaceae. Our central hypothesis is that siderophore analogues anchor copolymers on the outer-membrane of Enterobacteriaceae with high selectivity over mammalian cells, and that the resulting blockage of the siderophore receptor, coupled with the charge of the polymer backbone, will kill the bacteria. The overall objective of this application is to synthesize a new family of co-polymers incorporating enterobactin and aerobactin anchors and evaluate their potential as antibiotic drugs. The rationale for the proposed research is that the availability of more powerful antibiotics and antibiotics with novel modes of actions is necessary to treat increasingly prevalent bacterial pathogens that are resistant to current drugs. We plan to accomplish our objectives by pursuing the following Specific Aims: 1) Determine the effect of the structure of the co-polymers grafted with enterobactin analogues on the material's antimicrobial effect; 2) Synthesize co-polymers grafted with aerobactin analogues and evaluate in vitro their potential as antimicrobial agents; and 3) Evaluate the potential of the siderophore-grafted copolymers to treat Enterobacteriaceae in experimental animal models of skin and skin structure as well as intra-abdominal infection.This research is significant because it aims to develop a new class of antibiotics which exploits a novel mechanism of action that targets microorganisms which present urgent and serious threats. Our approach is innovative because we are exploiting the siderophore uptake system of bacteria to generate a novel class of targeted antimicrobial polymers with enhanced antibiotic activity and therapeutic index. No antimicrobial polymer including a siderophore as a targeting vector has been described. Yet, the substantially greater antimicrobial activity of sideromycins compared to antimicrobial peptides strongly suggests that by grafting siderophores onto antimicrobial polymers, the activity of the latter will also be greatly increased.
The proposed research is relevant to public health because it will provide new antibiotics for the treatment of bacterial infections. These antibiotics function via a novel mechanism of actions and are effective against carbapenem-resistant strains and ESBL strains of Enterobacteriacae.
