Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria
| Main Author: | |
|---|---|
| Language: | English |
| Published: |
Case Western Reserve University School of Graduate Studies / OhioLINK
2017
|
| Subjects: | |
| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case149071553255931 |
| id |
ndltd-OhioLink-oai-etd.ohiolink.edu-case149071553255931 |
|---|---|
| record_format |
oai_dc |
| spelling |
ndltd-OhioLink-oai-etd.ohiolink.edu-case1490715532559312021-08-03T07:01:09Z Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria Guzzo, Marissa Blaire Microbiology The increasing frequency of MDR- and XDR-bacterial infections continues to pose a serious threat to global public health. This concern has not only intensified with the reduced efficacy of currently available treatments but with the significant decline in drug development and discovery. Through knowledge and understanding of bacterialintrinsic molecular resistance mechanisms, an emerging concept of “targeting resistance," or potentiation, has gained much interest as a means of re(sensitizing) pathogenic bacteria to available antibiotics. With a renewed interest in reviving the use of antifolates, such as sulfonamides, in the treatment of Mycobacterium tuberculosis (Mtb) infections, our lab developed a chemo-genomic screening approach for determining antifolate resistance determinants in mycobacterial species. We found that disruption of 5,10-methenyltetrahydrofolate (5,10-CH+-H4PteGlun) synthetase (MTHFS), an enzyme responsible for the conversion of 5-formyltetrahydrofolate (5-CHO-H4PteGlun, folinic acid) to 5,10-CH+-H4PteGlun in the folate-dependent one-carbon (1C) metabolic network led to severe defects in cellular folate homeostasis thus weakening the intrinsic antifolate resistance in both Mycobacterium smegmatis and Escherichia coli resulting in enhanced sensitivity to sulfonamides.Further investigation into folate mediated 1C metabolism led to the discovery of a novel mechanism of intrinsic sulfonamide resistance referred to as the methylfolate (MF) trap. Until now, this phenomenon has only been characterized in mammals as a means of explaining the relationship of Vitamin B12 (VB12), folate, and homocysteine (Hcy) homeostasis in many medical conditions such as anemia, neural tube defects, and Alzheimer’s dementia. This trap occurs as a result of defects in the multi-cycling reaction catalyzed by the B12-dependent methionine synthase (MetH). We demonstrate that in the presence of sulfonamide, MF trap induction, either through VB12 deficiency and/or mutations affecting MetH enzymatic activity, causes impaired homeostasis of folate and related metabolites as well as the cytotoxic accumulation of Hcy-thiolactone. This metabolic blockage ultimately leads to thymineless death rendering pathogenic bacteria, such as M. tuberculosis, E. coli, Pseudomonas aeruginosa, and Salmonella typhimurium, more susceptible to existing sulfonamides. We also provide proof-of-concept demonstrating that chemical induction of the MF trap by inhibiting VB12 uptake represents a novel method of potentiation by enhancing the antimicrobial activity of available, clinically approved sulfonamides. 2017-06-06 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case149071553255931 http://rave.ohiolink.edu/etdc/view?acc_num=case149071553255931 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Microbiology |
| spellingShingle |
Microbiology Guzzo, Marissa Blaire Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria |
| author |
Guzzo, Marissa Blaire |
| author_facet |
Guzzo, Marissa Blaire |
| author_sort |
Guzzo, Marissa Blaire |
| title |
Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria |
| title_short |
Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria |
| title_full |
Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria |
| title_fullStr |
Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria |
| title_full_unstemmed |
Molecular Mechanisms Underlying the Intrinsic Sulfonamide Resistance in Bacteria |
| title_sort |
molecular mechanisms underlying the intrinsic sulfonamide resistance in bacteria |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2017 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case149071553255931 |
| work_keys_str_mv |
AT guzzomarissablaire molecularmechanismsunderlyingtheintrinsicsulfonamideresistanceinbacteria |
| _version_ |
1719451757125304320 |