ANTIBIOTIC DISCOVERY AND INFECTION TREATMENT AND PREVENTION

As antimicrobial resistance proliferates, standard treatments for bacterial infections are rendered ineffective. There is therefore a need to both prevent infections and develop new treatment options. This need is especially urgent for priority pathogens like methicillin-resistant strains of Staphylococcus aureus (MRSA). Developing new antibiotics is difficult for a variety of reasons, including virulence traits like the formation of biofilms, surface-associated bacterial communities that are less susceptible to antibiotics. Here we used biofilms to our advantage, since their formation is stimulated when bacteria are exposed to sub-lethal concentrations of antibiotics, allowing us to screen for compounds with antimicrobial activity that would be missed with traditional methods. Using this approach, we identified the anti-inflammatory compound BAY 11-7082 as an antibiotic. We showed that it inhibits growth of priority pathogens including MRSA and provide evidence to suggest it has a novel (and potentially multifaceted) mechanism. We also found it re-sensitizes MRSA to inexpensive and readily available β-lactam antibiotics like penicillin G. This finding was of particular interest since using antibiotic adjuvants in combination with existing antibiotics provides a promising and complementary strategy to antibiotic discovery. We showed that wall teichoic acids, polymer chains anchored to the S. aureus cell wall, were required for sensitization to occur; however, unlike existing adjuvants, BAY 11-7082 did not appear to impact cell morphology or division, suggesting it instead targets a factor of β-lactam resistance that may be less well understood. Lastly, we examined the impact of common surgical antiseptics on bacterial growth and biofilm formation, with a goal of preventing infections following joint replacement. We found these solutions to be effective; however, it is important to define the concentrations at which they inhibit microbial growth in vivo, since sub-lethal concentrations stimulate biofilm formation. Taken together, the findings in this thesis bolster our understanding of how to reduce and treat resistant infections.

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