With the “age of antibiotics” in the 1940s, many believed that we had conquered pathogenic microbes. However, it quickly became apparent that the ability of bacteria to evolve resistance had been sorely underestimated. Today, infectious diseases are the leading cause of death in low-income countries and the death toll is projected to outpace cancer in the United States by 2050. While antibacterial resistance has become increasingly common, FDA approval of antibacterial drug candidates has declined: only three novel classes of antimicrobials were introduced in the last four decades. Unfortunately, these new antibacterial agents are less effective than those identified in the first half of the last century and the majority of infections today are treated with antibiotic classes discovered prior to 1960. Given the dearth of new drug discoveries and the facile evolution of microbial resistance, some fear that we are entering a “post-antibiotic era.”
Most known antibiotics are compounds discovered from microorganisms. Microbes interact with their neighbors through a complex web of communication and warfare, largely by production of secondary metabolites (natural products). Most of the antimicrobial natural products identified to date are bactericidal, strategies that put selective pressure on the bacterium to respond with generation of resistance. Recently, we have begun to understand that bacteria produce myriad compounds not just for defense, but also for synergistic functions. The importance of these interactions is highlighted by the fact that an estimated 99% of all bacteria cannot be cultured under standard laboratory conditions, suggesting that there are unknown factors provided by interactions with neighboring organisms that are essential for proliferation.
To develop antibiotics that possess potency and long-term efficacy, it will be critical to identify inhibition strategies that evade current resistance mechanisms and apply less evolutionary pressure to slow the development of resistance. To address this mounting challenge, the Carlson Group unites tools from chemistry and biology to explore and exploit the master regulators of microbial behavior. We are pursuing three intersecting objectives to generate a deeper understanding of how to blind, silence and eliminate bacteria as summarized in Figure 1.