Bacterial Pathogenesis and Antimicrobial Drug Resistance

Antimicrobial resistance poses a major challenge to human health. Since their introduction in the 1940s, antibiotics have transformed healthcare and reduced the morbidity and mortality of diverse infectious diseases. However, many bacterial species are highly adept at rapidly developing resistance to existing and novel drugs, leaving few effective treatment options. Understanding molecular mechanisms of resistance as well as their impact on virulence of the organisms is critical for developing novel intervention strategies.

Research in the division on antimicrobial resistance and pathogenesis centers on both Gram-positive and Gram-negative organisms. This includes a research focus on staphylococci, most notably Staphylococcus aureus, a major cause of morbidity and mortality in both hospital- and community-acquired infections. The recent increase in antimicrobial resistance among strains of S. aureus has heightened concern about our limited understanding of the pathogenesis as well as the limited options available for the treatment of these life-threatening infections. Dr. Lowy's laboratory has studied: (1) the role of staphylococcal proteins in the initiation of prosthetic device infections; (2) demographic and molecular epidemiologic investigations of staphylococcal colonization and disease in populations at high risk of S. aureus infection; (3) bacterial and cellular gene expression in murine models of infection; and (4) investigations of the biology of nasal colonization with S. aureus. Other work focuses on elucidating the role of S. aureus cytotoxicity on bacteremia outcomes.

Antimicrobial resistance in Gram-negative infections provide a particular treatment challenge. Resistance genes may rapidly spread via horizontal transfer of plasmids between organisms. Moreover, few effective drugs are available to treat carbapenem-resistant Enterobacteriaceae (CRE), including the older polymyxins associated with high toxicity. While novel carbapenemase inhibitors show promise and more specifically target CREs, recent experience has documented rapid development of resistance to these novel combinations during treatment of patients. Dr. Uhlemann's group focuses on identifying novel molecular markers of resistance to a broad range of antibiotics targeting CRE and other multi-drug resistant bacteria. Their translational approach includes molecular epidemiology studies on CRE, bacterial genomics, and in vitro studies on the structure-function relationship of putative drug-resistance conferring mutations.

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