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From Antimicrobial Discovery to Clinical Diagnostics: Applications of Bacterial Cytological Profiling

  • Author(s): Quach, Diana T.
  • Advisor(s): Pogliano, Kit
  • Hasty, Jeff
  • et al.
Abstract

The discovery and widespread usage of antibiotics has drastically improved human health in the 20th century. Unfortunately, the extensive use and misuse of antimicrobial drugs led to the emergence and spread of drug-resistant pathogens. The threat from increasingly resistant pathogens is exacerbated by the decline in antibacterial drug discovery due to regulatory burden, low profit margins compared to other drugs as well as investments in antibiotic discovery platforms that ultimately proved unproductive. Two approaches aimed at ameliorating this threat include the (1) development of new therapies and antimicrobial agents and (2) implementation of policies to reduce the emergence and spread of resistant pathogens (e.g. using existing antimicrobials more effectively) in a set of strategies known as antimicrobial stewardship. Bacterial cytological profiling (BCP), a microscopy-based technique which creates profiles from the measurement of changes in cellular architecture following antibiotic treatment, contributes to both the discovery of antimicrobials as well as antimicrobial stewardship. BCP had been shown to rapidly identify cellular pathway targeted by antibacterial molecules, thereby demonstrating the utility of BCP in identifying the mode of action (MOA) of unknown compounds in order to prioritize compounds of interest for further development.

Here, I show that BCP is a flexible tool that can be applied to study the MOA of antibiotics for Pseudomonas aeruginosa. Additionally, I have developed a rapid, antimicrobial susceptibility test based on BCP (AST-BCP) in order to determine the appropriate antimicrobial therapy in a timely manner thereby reserving antibiotics in the last line of defense for cases which require them. AST-BCP was able to accurately determine the susceptibility profiles for a set of Staphylcoccus aureus clinical isolates and a smaller set of P. aeruginosa strains suggesting that this platform would be appropriate surrogate for traditional susceptibility tests. Finally, I discuss the development of a user-friendly data analysis platform, designed specifically for BCP datasets. The potential application of BCP spans multiple research areas from antimicrobial discovery to resistance identification and is a powerful tool for investigating antimicrobial compounds and clinical pathogens.

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