This dissertation describes the synthesis and antimicrobial use of a series of half-sandwich Ir(III), Rh(III), Co(III) amino acid and ethylenediamine complexes. This investigation focuses on the formulation (ηn-arene)M(L)X, (L = ethylenediamine or α-amino carboxylate), (M= Ir, Rh, Ru, Co). Arene, Ligand and metal center variations were designed to tailor antimicrobial activity specific for each organism studied (Staphylococcus aureus or Mycobacteria). Each of the D/L-amino acids formed a diasteromeric complex with chiral centers on both the metal center and amino acid ligand. The unique chirality of each center elicits different antimicrobial activity against the Mycobacteria studied. The metal center (M), arene ligand (ηn-arene), and amino acid (aa), were changed independently and studied for the antimicrobial activity. In a similar fashion, each of the complexes modified with ethylenediamine and diamine derivatives were studied for their antimicrobial activity against S.aureus. All complexes were synthesized,characterized by nuclear magnetic resonance (NMR), high-resolution mass spectroscopy (HRMS), single-crystal X-ray diffraction, and elemental analysis.
During the course of this work it was found that the amino acid complexes with all metal centers were specific for antimicrobial activity against all types of Mycobacteria, while the diamine derivatives were active against different strains of S.aureus. Acitvity was measured to be as low as 2 ug/mL respectively depending on the complex used. A structure activity relationship was developed to determine what combinations of ligand, metal and arene were necessary to achieve the highest antimicrobial activity. The optimal arene R-chain length for CpR was determined to be R=hexyl for all complexes studied. The most active amino acidcomplex was determined to be that of L-phenylglycine for Mycobacteria, the cis-1,2-diaminocyclohexane complex is the most active ligand against S.aureus. Each metal center had similar activity levels. Toxicological studies were performed to test their viablity to be used in mammalian systems. The complexes with the highest activity were studied against several mammailan cell lines and revealed that mammailan cells were undergoing normal cellular processes at up to 40 times the minimal inhibitory concentration (MIC). A study of the MOA or mechanism of action revealed the ability of the amino acid complexes to affect the peptidyl transferase region on the 23s ribosomal subunit of M.smegmatis. This was accomplished by isolating resistant strains of M.smegmatis towards the most effective complex (Cp*hexyl)Ir(L-phenylglycine)-Cl. Cross drug resistance of these mutants was shown with clarithromycin. The DNA of the 23s ribosomal subunit was sequenced revealing a deletion/insertion mutation within domain V (bases 2057-2058). / Ph. D. / This disserataion discribes the discovery of laboratory created synthetic organometallic molecules (carbon and metal containing molecules) that exhibit antimicrobial properties. Each of these molecules are specifically designed and tailored to combat several infectious and antibiotic resistant disesaes. The different and unique compositions of each of these novel molecules allows for a potentially new class of antibiotics. Each of these organometallic molecules was able to be tailored to comabt either Staphylococcus aureus or Mycobacteria. Each of these bacteria have significant health risks and are a growing threat to public health. During the course of this work it was found that the molecules containing amino-acids were specific for activity against all types of Mycobacteria studied. The diamine containing molecules were specific for gram positive bacteria (Staphylococcus aureus). Actvity to confirm this activity was measured by MIC (Minimal inhibitory concetration). This is the amount of the molecule that is needed to stop the growth of the bacteria studied. The complexes with the highest activity were tested for their potential hazardous interactions with mammalian cells. It was revealed that not only do these molecules have activity in combating potentially deadly pathogens but they are not active against several mammalian cell lines. This shows that these can be possible candidates for a new line of antimicriobial drugs.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/79414 |
| Date | 25 September 2017 |
| Creators | Karpin, George W. |
| Contributors | Chemistry, Merola, Joseph S., Santos, Webster L., Falkinham, Joseph O. III, Long, Gary L. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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