Bacterial DNA Adenine Methyltransferase as a Novel Drug Target for Antibiotics: Current Status and Future Drug Discovery Challenges

Omeershffudin, Umairah Natasya Mohd; Kumar, Suresh

doi:10.20546/ijcmas.2019.804.290

Cited by 2 publications

(3 citation statements)

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“… 19 , 20 Furthermore, by selectively hindering the repair pathway, it is possible to obtain improved antibiotics. 21 For instance, hydrogen peroxide used in ion beam therapy for the treatment of cancer has been shown to stabilize base-pairs, making it difficult for enzymes to flip out the base during nucleotide excision repair (NER) and mismatch repair (MMR). 22 Hence, inhibiting the DNA repair machinery can kill cancer cells and may thus provide a route to treatment.…”

Section: Introductionmentioning

confidence: 99%

“…For example, the DNA repair machinery does not work efficiently in patients with xeroderma pigmentosum . Recently, defects in DNA glycosylases have been linked with colorectal cancer. , Furthermore, by selectively hindering the repair pathway, it is possible to obtain improved antibiotics . For instance, hydrogen peroxide used in ion beam therapy for the treatment of cancer has been shown to stabilize base-pairs, making it difficult for enzymes to flip out the base during nucleotide excision repair (NER) and mismatch repair (MMR) .…”

Section: Introductionmentioning

confidence: 99%

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Energy Landscapes for Base-Flipping in a Model DNA Duplex

2022

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We explore the process of base-flipping for four central bases, adenine, guanine, cytosine, and thymine, in a deoxyribonucleic acid (DNA) duplex using the energy landscape perspective. NMR imino-proton exchange and fluorescence correlation spectroscopy studies have been used in previous experiments to obtain lifetimes for bases in paired and extrahelical states. However, the difference of almost 4 orders of magnitude in the base-flipping rates obtained by the two methods implies that they are exploring different pathways and possibly different open states. Our results support the previous suggestion that minor groove opening may be favored by distortions in the DNA backbone and reveal links between sequence effects and the direction of opening, i.e., whether the base flips toward the major or the minor groove side. In particular, base flipping along the minor groove pathway was found to align toward the 5′ side of the backbone. We find that bases align toward the 3′ side of the backbone when flipping along the major groove pathway. However, in some cases for cytosine and thymine, the base flipping along the major groove pathway also aligns toward the 5′ side. The sequence effect may be caused by the polar interactions between the flipping-base and its neighboring bases on either of the strands. For guanine flipping toward the minor groove side, we find that the equilibrium constant for opening is large compared to flipping via the major groove. We find that the estimated rates of base opening, and hence the lifetimes of the closed state, obtained for thymine flipping through small and large angles along the major groove differ by 6 orders of magnitude, whereas for thymine flipping through small angles along the minor groove and large angles along the major groove, the rates differ by 3 orders of magnitude.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Energy Landscapes for Base-Flipping in a Model DNA Duplex

2022

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“…As discussed above, the frequent use of streptomycin in plague treatment may have played an important role in the emergence of this mutation. Since drugs mediate gene mutations, vaccines and antibiotics targeting novel gene points (such as DNA adenine methyltransferase) may be an inevitable choice for defeating the bacteria [68].…”

Section: Discussionmentioning

confidence: 99%

Yersinia pestis antibiotic resistance: a systematic review

Lei

Kumar²

2022

PHRP

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Yersinia pestis, the cause of plague and a potential biological weapon, has always been a threatening pathogen. Some strains of Y. pestis have varying degrees of antibiotic resistance. Thus, this systematic review was conducted to alert clinicians to this pathogen’s potential antimicrobial resistance. A review of the literature was conducted for experimental reports and systematic reviews on the topics of plague, Y. pestis, and antibiotic resistance. From 1995 to 2021, 7 Y. pestis isolates with 4 antibiotic resistance mechanisms were reported. In Y. pestis 17/95, 16/95, and 2180H, resistance was mediated by transferable plasmids. Each plasmid contained resistance genes encoded within specific transposons. Strain 17/95 presented multiple drug resistance, since plasmid 1202 contained 10 resistance determinants. Strains 16/95 and 2180H showed single antibiotic resistance because both additional plasmids in these strains carried only 1 antimicrobial determinant. Strains 12/87, S19960127, 56/13, and 59/13 exhibited streptomycin resistance due to an rpsl gene mutation, a novel mechanism that was discovered recently. Y. pestis can acquire antibiotic resistance in nature not only via conjugative transfer of antimicrobial-resistant plasmids from other bacteria, but also by gene point mutations. Global surveillance should be strengthened to identify antibiotic-resistant Y. pestis strains by whole-genome sequencing and drug susceptibility testing.

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Bacterial DNA Adenine Methyltransferase as a Novel Drug Target for Antibiotics: Current Status and Future Drug Discovery Challenges

Cited by 2 publications

References 36 publications

Energy Landscapes for Base-Flipping in a Model DNA Duplex

Energy Landscapes for Base-Flipping in a Model DNA Duplex

Yersinia pestis antibiotic resistance: a systematic review

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