Blocking the Antimicrobial Transport Pathway to Eradicate Multidrug-Resistant Bacteria in Otitis Media

While most adults can clear a middle ear infection (called otitis media, or OM) with their innate immune response, children under the age of five are more susceptible to these infections, resulting in frequent pediatrician visits and reoccurring infections. In infants, the bacteria that typically causes this infection, called non-typeable Haemophilius influenzae (NTHi), moves from the part of the throat behind the nose to the middle ear. Colonization by these bacteria leads to inflammation and fluid accumulation in the ear and can result in tearing or perforation of the eardrum. Repeated infections can result in problems in hearing and, in some cases, cause developmental issues such as delayed language. Antibiotics are the primary approach to treating OM, but many bacteria have developed resistance to multiple antibiotics, making infections more difficult to clear. Otitis media is the most common respiratory tract infection of infancy and early childhood. With an estimated 2.2 million episodes in the US annually, OM is the main reason children receive antibiotics. In the last 15 years, bacterial responsiveness to antibiotic treatment has declined markedly, but scientists have made only modest progress in developing new antibacterial agents. Children carrying antibiotic-resistant NTHi are treated with increased doses of antibiotics, further risking bacterial resistance. These patients in turn run the risk of spreading resistant pathogens (disease-causing bacteria) to community members in daycare and at home. New antibiotics cannot solve this problem in a lasting way, since these pathogens will develop resistance to new antibiotics over time, creating superbugs. Because of the frequency of infections and increasing antibiotic resistance, finding new ways to treat these upper respiratory tract infections is paramount. As a Hartwell Individual Biomedical Researcher, I will use a strain of NTHi colonized from a patient with acute OM to design inhibitors that will target and destroy the pathogen through its own nutrient uptake system. This approach is innovative because I will treat antimicrobial resistant bacterial infections with inhibitors that target the nutrient uptake system in bacteria but not in the host. Bacteria use membrane proteins to shuttle nutrients across cell membranes. A subset of these proteins, called importers, are abundant in bacteria and transport a variety of necessary nutrients acquired from the environment. This mechanism of import is critical to bacteria’s survival, especially for pathogens, that reside within the host. Most important, these importers are present in bacteria but not in humans, making them a unique target for inhibitors. If successful, my approach will provide a powerful tool in conjunction with the host innate immune response for clearing pathogenic bacterial infections that cause OM. Inhibitors that specifically target the pathogens nutrient system will work as an alternative therapy to decrease the development of multiple antibiotic-resistant bacteria.