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Document Type

Campus-Only Access for Five (5) Years

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Animal Biotechnology & Biomedical Sciences

Year Degree Awarded

2017

Month Degree Awarded

February

First Advisor

Margaret A. Riley

Second Advisor

Susan B. Leschine

Third Advisor

Robert L. Dorit

Fourth Advisor

Annette Wysocki

Subject Categories

Amino Acids, Peptides, and Proteins | Bacterial Infections and Mycoses | Biomedical and Dental Materials | Biotechnology | Pathogenic Microbiology | Therapeutics

Abstract

The emergence and spread of antibiotic resistance has created one of the greatest challenges in fighting infectious disease. We address the rise of antibiotic-resistant pathogens by examining the evolutionary history of a class of resistance determinants, the SHV b-lactamases. We isolated the genes that encode the SHV beta-lactamases (blaSHV genes) from clinical settings and from an environment essentially devoid of antibiotic use. Our data suggests that, counter to current dogma, the use of antibiotics in the clinic is not creating these resistance genes; genes for antibiotic resistance already exist in nature and our use of antibiotics in clinical settings is simply selecting for them. This study underscores the breadth of our antibiotic resistance challenge and reveals that we must take the collateral impacts of our antimicrobial use into account during antibiotic development.

Bearing this in mind, we propose that bacteriocins possess all of the requisite features to become our next generation of antimicrobials. To demonstrate the power of these narrow-spectrum bacterial toxins, we target an infection with high rates of antibiotic resistance and few efficacious antimicrobial strategies; catheter-associated urinary tract infections (CAUTI). CAUTI are the leading cause of hospital-acquired infections (HAIs). The Centers for Medicare and Medicaid Services (CMS) has recently categorized CAUTI as a preventable HAI and has enacted new reimbursement guidelines, which do not allow hospitals to be reimbursed for costs associated with CAUTI. Due to this, there is significant interest in the development of prophylactic measures to prevent these infections. The main causative pathogen of CAUTI is uropathogenic E. coli (UPEC). Colicins are bacteriocins produced by and active against E. coli. We assessed the efficacy of colicins against UPEC strains compared with traditional antibiotics used to treat urinary tract infections. We found that colicins were just as effective as antibiotics with additional features that made them a better choice for use as a prophylactic against CAUTI.

Urinary catheters are inserted with the aid of lubricating jelly. We created a CAUTI prophylactic by incorporating a novel colicin (colicin SR4) into a lubricant commonly used in urinary catheterization. We found that in vitro, we were able to prevent catheter contamination as well as kill any cells present in the catheter environment. This lubricant maintained antimicrobial efficacy over relevant temperatures and pHs associated with CAUTI. This study argues that colicins represent a sound antimicrobial approach for the prevention of CAUTI.

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