Date of Award

Fall 12-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry & Biochemistry

Program/Concentration

Chemistry

Committee Director

Erin B. Purcell

Committee Member

Steven M. Pascal

Committee Member

James W. Lee

Committee Member

Christopher Osgood

Abstract

Anaerobic Gram-positive bacteria are not a well-characterized group but include many human pathogens that are resilient against stresses caused by the human immune system or by antibiotic treatment. This dissertation investigated the survival mechanisms of two clinically relevant Gram-positive organisms, Clostridioides difficile and Cutibacterium acnes under extracellular stresses. The response of the opportunistic skin pathogen Cutibacterium acnes to nanosecond electric pulses is characterized and found that growth in a biofilm, which usually protects bacteria from stress, renders this species more killable by this treatment. In addition, the stringent response (SR), a conserved bacterial stress survival mechanism, is studied in the intestinal pathogen Clostridioides difficile. The SR contributes to antibiotic tolerance and virulence in many pathogens, but there is no homogeneity in its operation and regulation among diverse bacterial species. The SR is driven by the guanosine nucleotide signaling alarmones, (pp)pGpp, that are synthesized by conserved enzymes. We identified environmental cues that induce clostridial synthetase expression and implicated (pp)pGpp signaling in antibiotic survival. Interestingly, we have discovered that both the clostridial stringent response synthetases synthesize pGpp rather than pppGpp/ppGpp as the only alarmone, which is unique among bacteria that use the SR. C. difficile must cope with rapidly changing and diverse gastrointestinal environments and survive antibiotic treatment to establish Clostridioides difficile infection (CDI). The results from this study elucidated its survival mechanism in hostile environments and offer significant insights to develop targeted therapeutics against CDI.

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DOI

10.25777/jm83-ba64

ISBN

9798762197335

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