Improving antibiotic activity by manipulating bacterial reactive oxygen species metabolism
Winkler, Jonathan Alexander
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The discovery of antibiotics was one of the most important medical breakthroughs of the twentieth century, having a broad impact on overall life expectancy and public health. Unfortunately, antibiotic discovery has slowed significantly in recent times and has failed to match the rising incidence of antibiotic-resistant pathogens. Gram-negative pathogens are a particularly troublesome threat, primarily because these bacteria possess an outer membrane that prevents many antibiotics from accessing their primary cellular targets. While the discovery of novel antibiotics could help to address these issues, alternative strategies, such as improving the activity of preexisting antibiotics, are also needed. Bactericidal antibiotics have recently been shown to share a common mechanism of cell death, despite having different primary, cellular targets. This shared mechanism involves the metabolic production of reactive oxygen species (ROS), which can damage proteins, lipids, and nucleic acids, and can ultimately result in bacterial cell death. The body of work described here shows that this common mechanism can be exploited to improve antibiotic activity, regardless of the antibiotic's primary mode of action. First, I will describe how bacterial metabolism can be predictably perturbed to increase endogenous ROS production, and that increasing endogenous ROS is sufficient to enhance bacterial sensitivity to treatments with ROS-generating biocides, antibiotics, and immune cell attack. I will then describe work indicating that an ancient antimicrobial agent, silver salts, can also increase endogenous ROS production and potentiate the activity of multiple antibiotic classes. Furthermore, I show that silver salts can increase the outer membrane permeability of a Gram-negative organism. This property is exploited to enable vancomycin, an antibiotic that is specific for Gram-positive bacteria, to work against a Gram-negative organism. Together, this body of work demonstrates that bacterial ROS metabolism can be exploited effectively to enhance. antibiotic activity, which ultimately could result in the discovery and development of novel antimicrobial agents.
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