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Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization
Thesis (PhD)--Stellenbosch University, 2019.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2019
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| _version_ | 1867614031185969152 |
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| access_status_str | Open Access |
| author | Jana, Collins Edward |
| author2 | Strauss, Erick |
| author_browse | Jana, Collins Edward Strauss, Erick |
| author_facet | Strauss, Erick Jana, Collins Edward |
| author_sort | Jana, Collins Edward |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2019. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/106973 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:45:33.890Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/106973 Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization Jana, Collins Edward Strauss, Erick De Villiers, Marianne Stellenbosch University. Faculty of Science. Dept. of Biochemistry. Anti-infective agents Coenzymes -- Synthesis -- Inhibitors Antimetabolites Mechanism of action (Biochemistry) Sulfonamides UCTD Thesis (PhD)--Stellenbosch University, 2019. ENGLISH ABSTRACT: Though tremendous progress has been made in the development of antibacterial drugs, the evolution of antimicrobial resistance is a serious problem that is affecting the successful prevention and treatment of various infections caused by microbial pathogens. Taking this into consideration, the need for new antimicrobials is of paramount importance. Since the B-vitamin pantothenate promotes the growth of microbes, analogues of this compound that may act as antimetabolites have been synthesized and tested for their inhibitory properties against bacterial growth. N-substituted pantoyltauramides (PanSulfAms) are a class of pantothenate analogues previously synthesized by various research groups in the 1940s. These analogues demonstrated promising inhibition of the proliferation of avian malaria parasites as well as showing good antibacterial activities against Streptococcus pyogenes. In this study, the chemical and structural diversity of these analogues was expanded by preparing PanSulfAms in which various amide moieties were introduced to the sulfonic acid group of taurine. These compounds were subsequently used to produce fourteen PanSulfAms that were investigated for their potential as antibacterial agents. The growth inhibitory activities of the synthesized PanSulfAms were first investigated against Escherichia coli and Staphylococcus aureus both as models of Gram-negative and Gram-positive bacteria respectively, and because these compounds have never been investigated on these microbes. We also investigated the link between the organisms’ pantothenate kinase (PanK) types and the observed growth inhibition to ascertain whether this relates to the compounds’ mode of action. In this study, we have shown for the first time that PanSulfAms have the potential to inhibit S. aureus growth, but not that of E. coli. In addition, we have also performed the first detailed comparative kinetic analysis of PanSulfAms that cause S. aureus growth inhibition, demonstrating that PanK type directs the mode of action of these compounds. Finally, the PanSulfAms were studied for their ability to inhibit CoA biosynthesis. We show that their impact is compound-specific and relates to their interaction with the various CoA biosynthetic enzymes. We demonstrate for the first time that certain phosphorylated PanSulfAms act as inhibitors of the PPCS activity of the bifunctional CoaBC protein, and that, in combination with a specific interaction with the S. aureus PanK, has strong negative impact on the rate of CoA biosynthesis that likely contributes to their overall mode of action. AFRIKAANS OPSOMMING: Alhoewel geweldige vordering gemaak is met die ontwikkeling van antibakteriese middels, is die ontwikkeling van antimikrobiese weerstandigheid 'n ernstige probleem wat die suksesvolle voorkoming en behandeling van verskillende infeksies wat deur mikrobiese patogene veroorsaak word, beïnvloed. Met inagneming hiervan is die behoefte aan nuwe antimikrobiese middels uiters belangrik. Aangesien die B-vitamien pantotenaat die groei van mikrobes bevorder, is analoë van hierdie verbinding wat as antimetaboliete kan dien gesintetiseer en getoets vir hul remmende eienskappe teen bakteriële groei. N-gesubstitueerde pantoyltauramiede (PanSulfAms) is 'n klas pantotenaat-analoë wat in die veertigerjare deur verskillende navorsingsgroepe gesintetiseer is. Hierdie analoë het belowende remming van die verspreiding van voëlmalaria-parasiete aangetoon, asook goeie antibakteriese aktiwiteite teen Streptococcus pyogenes. In hierdie studie is die chemiese en strukturele diversiteit van hierdie analoë uitgebrei deur PanSulfAms te sintetiseer waarin verskillende amiedgroepe aan die sulfonsuurgroep van taurien geheg is. Hierdie verbindings is vervolgens gebruik om veertien PanSulfAms te vervaardig wat ondersoek is na hul potensiaal as antibakteriese middels. Die groei-remmende aktiwiteite van die gesintetiseerde PanSulfAms is eers ondersoek teen Escherichia coli en Staphylococcus aureus, beide as modelle van onderskeidelik Gram-negatiewe en Gram-positiewe bakterieë, en omdat hierdie verbindings nog nooit op hierdie mikrobes ondersoek is nie. Ons het ook die verband tussen die organismes se pantotenaat kinase (PanK) ensieme en die waargenome groei-remming ondersoek om vas te stel of dit verband hou met die werking van die verbindings. In hierdie studie het ons vir die eerste keer aangetoon dat PanSulfAms die potensiaal het om S. aureus-groei te belemmer, maar nie dié van E. coli nie. Daarbenewens het ons ook die eerste gedetailleerde vergelykende kinetiese analise van PanSulfAms uitgevoer wat die remming van S. aureus groei veroorsaak. Dit toon dat die organisme se PanK-tipe die werking van hierdie verbindings rig. Laastens is die PanSulfAms bestudeer op grond van hul vermoë om CoA-biosintese te inhibeer. Ons toon aan dat die impak daarvan afhanklik is van die spesfieke verbinding en verband hou met hul interaksie met die verskillende CoA-biosintetiese ensieme. Ons demonstreer vir die eerste keer dat sekere gefosforileerde PanSulfAms optree as remmers van die PPCS-aktiwiteit van die bifunksionele CoaBC-proteïen, en dat dit, in kombinasie met 'n spesifieke interaksie met die S. aureus PanK, 'n sterk negatiewe invloed het op die tempo van CoA-biosintese. Dit dra waarskynlik by tot hul algemene werkingswyse. Doctorate 2019-11-26T20:39:14Z 2019-12-11T06:41:09Z 2021-06-30T03:00:11Z 2019-12 Thesis http://hdl.handle.net/10019.1/106973 en_ZA Stellenbosch University xviii, 158 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Anti-infective agents Coenzymes -- Synthesis -- Inhibitors Antimetabolites Mechanism of action (Biochemistry) Sulfonamides UCTD Jana, Collins Edward Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization |
| title | Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization |
| title_full | Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization |
| title_fullStr | Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization |
| title_full_unstemmed | Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization |
| title_short | Synthesis, profiling and mode of action studies of PanSulfAms as inhibitors of coenzyme a biosynthesis and utilization |
| title_sort | synthesis profiling and mode of action studies of pansulfams as inhibitors of coenzyme a biosynthesis and utilization |
| topic | Anti-infective agents Coenzymes -- Synthesis -- Inhibitors Antimetabolites Mechanism of action (Biochemistry) Sulfonamides UCTD |
| url | http://hdl.handle.net/10019.1/106973 |
| work_keys_str_mv | AT janacollinsedward synthesisprofilingandmodeofactionstudiesofpansulfamsasinhibitorsofcoenzymeabiosynthesisandutilization |