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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Heinrichs, David E.

Abstract

The Staphylococcus genus is comprised of over 40 bacterial species. The most well-studied species in this genus is the notorious human pathogen Staphylococcus aureus, a bacterium that produces coagulase among many other virulence factors. Since S. aureus is a major health burden and causes a plethora of diseases in humans, it has received significant attention and much research has been done to understand its biology to treat diseases caused by this pathogen. However, the coagulase-negative staphylococci (CoNS) make up most of the staphylococcal species and have received less attention since they are thought to have a lesser impact on human disease compared to S. aureus. However, recent research has begun to shed light on the importance of these species. In this thesis, I found that a number of CoNS including S. chromogenes, S. epidermidis, S. capitis, and S. pseudintermedius produce the small molecule 6-thioguanine (6-TG), and this molecule can antagonize S. aureus by inhibiting purine biosynthesis, an important metabolic pathway in many bacteria. By inhibiting this pathway, 6-TG reduced S. aureus growth and attenuated its virulence which improved S. aureus skin infection outcomes. Moreover, I found that S. aureus can become resistant to 6-TG through frameshift and missense mutations in a xanthine-uracil permease family protein, or single nucleotide polymorphisms in the enzyme hypoxanthine phosphoribosyltransferase. In addition to interactions with S. aureus, CoNS may also be pathogenic, and I demonstrated that the accessory gene regulator (Agr) controls virulence factors in the CoNS S. lugdunensis as it regulates the production of several toxins and increases its resistance to killing by immune effectors. Altogether, this research describes the impact that some CoNS can have on human health by producing molecules that antagonize S. aureus. On the other hand, it also describes mechanisms by which some CoNS may promote disease through quorum-sensing dependent control of virulence factor production.

Summary for Lay Audience

Staphylococcus aureus is a major health burden and causes a plethora of diseases in humans. Therefore, it has received significant attention and much research has been done to understand its biology to treat diseases caused by this pathogen. However, the coagulase-negative staphylococci (CoNS) make up most of the staphylococcal species and have received less attention since they are thought to have a lesser impact on human disease compared to S. aureus. However, recent research has begun to shed light on the importance of these species. In this thesis, I found that a number of CoNS produce 6-thioguanine (6-TG), and this molecule antagonizes S. aureus by inhibiting purine biosynthesis, an important metabolic pathway in many bacteria. As a result, 6-TG reduces S. aureus growth and reduced its ability to cause skin infections in mice. Moreover, I found that S. aureus can develop resistance against 6-TG through mutations in a specific permease and enzyme. However, CoNS may also cause disease on their own, and I demonstrated that a specific regulation system called Agr controls virulence factors in the CoNS S. lugdunensis. Agr controls the production of toxins and increases the ability of S. lugdunensis to resist killing by the immune system. Altogether, this research describes the impact that some CoNS can have on human health by producing molecules that antagonize S. aureus. On the other hand, it also describes mechanisms by which some CoNS may promote disease through quorum-sensing dependent control of virulence factor production.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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