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Publication Date

Fall 2016

Degree Type

Thesis - Campus Access Only

Degree Name

Master of Science (MS)

Department

Chemistry

Advisor

Laura C. Miller Conrad

Keywords

antibiotic resistance, colistin, high throughput screening, organic synthesis, Pseudomonas aeruginosa

Subject Areas

Chemistry; Cellular biology; Organic chemistry

Abstract

Pseudomonas aeruginosa is a gram-negative bacterium that causes hospital-acquired

infections. P. aeruginosa has a multitude of defense mechanisms that limit the effectiveness of antibiotics to combat the bacterium. A large number of antibiotics were developed over the 20th century, but overuse has helped contribute to the rise of antibiotic resistance. The Centers for Disease Control (CDC) has categorized P. aeruginosa as a “serious” threat among the top eighteen antibiotic-resistance bacterial threats identified in the US. Cationic antimicrobial peptides (CAPs), including colistin and polymyxin B, are currently utilized as last resort treatments for infections with multidrug-resistant strains of P. aeruginosa. Alarmingly, CAP-resistant strains of the bacterium have been encountered. Resistance occurs with the up regulation of the arnBCADTEF operon, leading to the modification of the outer membrane. This modification decreases the net negative charge on the outer membrane, which in turn lowers the affinity for the CAPs, blocking their entry into the cell. We are targeting inhibition of the first committed step of the pathway, catalyzed by ArnA. Successful inhibition of this enzyme with a small molecule will render the pathway nonfunctional, preventing outer membrane modification. The bacteria will thus remain susceptible to colistin, and a combination therapy of the ArnA inhibitor and colistin could be utilized against resistant strains.

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