Elucidating Polymyxin's Mode of Action and PrpA's (Polymyxin resistance protein A) Function in Acinetobacter baumannii Open Access

Liu, Sean (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/1544bp252?locale=en
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Abstract

Antibiotic resistance has become a major public health concern as the prevalence of multi-drug resistant pathogens continues to rise. Acinetobacter baumannii is a highly antibiotic resistant, nosocomial pathogen, that is a significant cause of ventilator-acquired pneumonia and other infections. Its ability to survive for prolonged periods under harsh conditions and to subvert the host immune system makes it difficult to combat. Although seldom used for decades due to their nephrotoxicity, polymyxins are now used for the treatment of A. baumannii infections as the last-resort drug therapy. Thus, it is crucial to understand how polymyxins kill bacteria, and the mechanisms the bacteria use to acquire resistance to these drugs and handicap the host innate immune system. I have shown that polymyxins kill A. baumannii through induction of a hydroxyl radical death pathway. Furthermore, I investigated the genetic basis of polymyxin B resistance in A. baumannii and identified PrpA (Polymyxin resistance protein A) as an important determinant. In the absence of prpA, A. baumannii was more susceptible to killing by polymyxin B. The mutant strain also has a defect in biofilm formation. Thorough analysis of PrpA will provide insight into a new mechanism that A. baumannii uses to evade killing, and potentially provide us with a new therapeutic target to treat future infections. Since PrpA is highly conserved, it is very likely that the same mechanism is utilized by other Gram-negative pathogens as well.

Table of Contents

INTRODUCTION...1

RESULTS & DISCUSSION...4

Figure 1...6

Figure 2...8

Figure 3...10

Figure 4...12

Figure 5...16

Figure 6...18

Figure 7...18

Figure 8...19

Figure 9...21

Figure 10...21

REFERENCES...26

SUPPLEMENTARY FIGURES...29

Sup. Figure 1...29

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