Kannan, Kartik
(2024)
Modulating the toxicity of polyamines in Staphylococcus aureus.
Undergraduate Thesis, University of Pittsburgh.
(Unpublished)
Abstract
USA300 is a recently discovered strain of community-acquired Methicillin-resistant S. aureus (CA-MRSA) that has been shown to be more virulent and transmissible than any other strain of MRSA. Like other strains of S. aureus, USA300 possesses resistance to β-lactam antibiotics; however, USA300’s increased potency is owed to its resistance to the naturally occurring polyamines spermine and spermidine. While spermine and spermidine are toxic to most strains of S. aureus, USA300 encodes a gene known as speG that confers resistance to these compounds. Because the target of spermine and spermidine is cytosolic and speG is a cytosolic protein, polyamine toxicity is thus limited by cellular uptake, with polyamine resistance additionally being conferred from within S. aureus cells.
This thesis thus serves to determine whether polyamine uptake can be increased to improve toxicity against USA300 clones. We have shown that unsaturated fatty acids such as palmitoleic acid, oleic acid, and linoleic acid are highly toxic to USA300 clones, presumably through the fatty acids’ incorporation into membrane phospholipids resulting in membrane disruption. In turn, we have shown that treatment of speG-deficient USA300 clones with combinations of palmitoleic acid, oleic acid, or linoleic acid with spermine results in higher levels of killing of these clones than the use of a fatty acid or spermine treatment alone. We have further shown that the treatment of wild-type USA300 clones with combinations of palmitoleic acid, oleic acid, or linoleic acid with the synthetic polyamines Bis(hexamethylene)triamine (HMTA) and Tris(3-aminopropyl)amine (TAPA) results in higher levels of killing of these clones that the use of a fatty acid or synthetic polyamine treatment alone. Additionally, this thesis has identified the S. aureus-encoded gene fakA as a contributor to exogenous unsaturated fatty acid toxicity, presumably due to fakA-dependent incorporation of exogenous fatty acids into the bacterium’s cellular membrane that could lead to increased membrane destabilization and the potential for increased polyamine uptake. As S. aureus is a skin and soft tissue infection, this thesis’s findings provide evidence that a combination of unsaturated fatty acids and polyamines could serve as the key components of a future topical treatment for USA300-caused infections.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
23 April 2024 |
| Date Type: |
Publication |
| Defense Date: |
5 April 2024 |
| Approval Date: |
23 April 2024 |
| Submission Date: |
19 April 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
37 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
David C. Frederick Honors College
Dietrich School of Arts and Sciences > Biological Sciences |
| Degree: |
BPhil - Bachelor of Philosophy |
| Thesis Type: |
Undergraduate Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
USA300, Staphylococcus aureus, MRSA, polyamines, spermine, unsaturated fatty acids, palmitoleic acid, oleic acid, linoleic acid |
| Date Deposited: |
23 Apr 2024 15:28 |
| Last Modified: |
23 Apr 2024 15:28 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46167 |
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