Structural Topology of a Small Multidrug Resistant Efflux Pump

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DESCRIPTION (provided by applicant): Multidrug resistance is a serious problem in the treatment of infectious diseases. The Institute of Allergy and Infectious Diseases indicates that many diseases are now becoming difficult to treat due to antimicrobial-resistant organisms. Some of these infectious diseases include HIV, tuberculosis, meningitis, staphylococcal infection, influenza, gonorrhea, Candida, and malaria. Currently 5-10% of hospital patients develop an infection, leading to 1.7 million infections, 99,000 patient deaths and ~$5 billion in annual healthcare costs (http://www.cdc.gov/ncidod/dhqp/ar.html). Just 15 years ago, only 12,000 people died from similar infections, indicating a significant elevation of the problem. After apparently finding cures for some of these diseases, the bacteria have evolved to resist treatments (antibiotics). In fact, > 70% of bacteria causing hospital infections are resistant to antibiotics commonly used to treat them. Members of the small multidrug resistance (SMR) protein family confer resistance to several quaternary ammonium compounds and other lipophilic cations that are commonly used in spray-fogging procedures for hospital rooms to reduce the number of airborne and surface bacteria. Continued overuse of such antibiotics and antiseptics will lead to other bacterial strains evolving even faster to resist common drugs used to treat disease and infection. The long-term goal of this research is to gain a molecular understanding of how diversity and complexity in both prokaryotic and eukaryotic cells have evolved in order to survive the insults of drugs. As a start, I will focus on the mechanism mediated through EmrE, an integral membrane protein within the SMR family. Although there are now greater than 250 members identified within this family, EmrE is the prototype for understanding the ion-coupled mechanism within several transporter families. Elucidating the resistance mechanism at molecular resolution in the native membrane environment is key to the design of new and more effective therapies to eradicate pathogenic organisms. The impact of this research will be to contribute a basic understanding toward how multidrug resistance is conferred to pathogenic organisms on a molecular level. The long-term goal of this project is to predict how drug binding might be altered in mutated strains of bacteria, so as to design new and better antibiotics in the event of multidrug resistance.