scholarly journals Type IA Topoisomerases as Targets for Infectious Disease Treatments

2021 ◽  
Vol 9 (1) ◽  
pp. 86
Author(s):  
Ahmed Seddek ◽  
Thirunavukkarasu Annamalai ◽  
Yuk-Ching Tse-Dinh
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase I ◽  
Drug Targets ◽  
Bacterial Infections ◽  
Treatment Options ◽  
Molecular Probes ◽  
Topological Features ◽  
Type Ia ◽  
New Antibiotics ◽  
Dna Strand

Infectious diseases are one of the main causes of death all over the world, with antimicrobial resistance presenting a great challenge. New antibiotics need to be developed to provide therapeutic treatment options, requiring novel drug targets to be identified and pursued. DNA topoisomerases control the topology of DNA via DNA cleavage–rejoining coupled to DNA strand passage. The change in DNA topological features must be controlled in vital processes including DNA replication, transcription, and DNA repair. Type IIA topoisomerases are well established targets for antibiotics. In this review, type IA topoisomerases in bacteria are discussed as potential targets for new antibiotics. In certain bacterial pathogens, topoisomerase I is the only type IA topoisomerase present, which makes it a valuable antibiotic target. This review will summarize recent attempts that have been made to identify inhibitors of bacterial topoisomerase I as potential leads for antibiotics and use of these inhibitors as molecular probes in cellular studies. Crystal structures of inhibitor–enzyme complexes and more in-depth knowledge of their mechanisms of actions will help to establish the structure–activity relationship of potential drug leads and develop potent and selective therapeutics that can aid in combating the drug resistant bacterial infections that threaten public health.

scholarly journals Crumbling the Castle: Targeting DNABII Proteins for Collapsing Bacterial Biofilms as a Therapeutic Approach to Treat Disease and Combat Antimicrobial Resistance

Antibiotics ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 104
Author(s):  
James V. Rogers ◽  
Veronica L. Hall ◽  
Charles C. McOsker
Keyword(s):  
Antimicrobial Resistance ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Defense Mechanism ◽  
Treatment Options ◽  
Bacterial Biofilms ◽  
Host Immune System ◽  
New Antibiotics ◽  
Financial Burdens ◽  
Global Threat

Antimicrobial resistance (AMR) is a concerning global threat that, if not addressed, could lead to increases in morbidity and mortality, coupled with societal and financial burdens. The emergence of AMR bacteria can be attributed, in part, to the decreased development of new antibiotics, increased misuse and overuse of existing antibiotics, and inadequate treatment options for biofilms formed during bacterial infections. Biofilms are complex microbiomes enshrouded in a self-produced extracellular polymeric substance (EPS) that is a primary defense mechanism of the resident microorganisms against antimicrobial agents and the host immune system. In addition to the physical protective EPS barrier, biofilm-resident bacteria exhibit tolerance mechanisms enabling persistence and the establishment of recurrent infections. As current antibiotics and therapeutics are becoming less effective in combating AMR, new innovative technologies are needed to address the growing AMR threat. This perspective article highlights such a product, CMTX-101, a humanized monoclonal antibody that targets a universal component of bacterial biofilms, leading to pathogen-agnostic rapid biofilm collapse and engaging three modes of action—the sensitization of bacteria to antibiotics, host immune enablement, and the suppression of site-specific tissue inflammation. CMTX-101 is a new tool used to enhance the effectiveness of existing, relatively inexpensive first-line antibiotics to fight infections while promoting antimicrobial stewardship.

scholarly journals Rapid Single-Cell Microbiological Analysis: Toward Precision Management of Infections and Dysbiosis

2019 ◽  
Vol 24 (6) ◽  
pp. 603-605
Author(s):  
Hui Li ◽  
Michael Morowitz ◽  
Neal Thomas ◽  
Pak Kin Wong
Keyword(s):  
Bacterial Infections ◽  
Treatment Options ◽  
Healthcare Providers ◽  
The Elderly ◽  
The United States ◽  
Microbiological Analysis ◽  
Global Health Issue ◽  
Improper Use ◽  
New Antibiotics ◽  
Prohibitive Cost

Bacterial infection is a leading cause of morbidity and mortality (from infants to the elderly) and accounts for more than $20 billion in healthcare costs in the United States each year. The pathogens responsible for many of the common infectious diseases, such as urinary tract infection (UTI) and ventilator-associated infections (VAIs), have proven to be highly adept in acquiring mechanisms of antimicrobial resistance. The use of broad-spectrum antibiotics by healthcare providers and the infiltration of antibiotics in the environment have accelerated the selection and growth of resistant pathogens. To further exacerbate the problem, the need for new antibiotics has far outpaced the development of new classes of antibiotics by the pharmaceutical industry (only two new classes of antibiotics have reached the market in the last 20 years), in large part due to prohibitive cost and historically poor return on investment to develop new antibiotics. Consequently, clinicians have limited treatment options, particularly in the neediest patients. To tackle this major global health issue, we are developing novel technological approaches for rapid definitive clinical microbiological analysis. These technologies will improve the clinical management of bacterial infections and reduce the improper use of antibiotics in current practice, hopefully limiting the spread of drug-resistant organisms.

scholarly journals Studies of bacterial topoisomerases I and III at the single-molecule level

2013 ◽  
Vol 41 (2) ◽  
pp. 571-575 ◽  
Author(s):  
Ksenia Terekhova ◽  
John F. Marko ◽  
Alfonso Mondragón
Keyword(s):  
Single Molecule ◽  
Topoisomerase I ◽  
Dna Topology ◽  
Biological Molecules ◽  
Single Molecule Level ◽  
Cellular Processes ◽  
Topoisomerase Iii ◽  
Type Ia ◽  
Dna Strand

Topoisomerases are the enzymes responsible for maintaining the supercoiled state of DNA in the cell and also for many other DNA-topology-associated reactions. Type IA enzymes alter DNA topology by breaking one DNA strand and passing another strand or strands through the break. Although all type IA topoisomerases are related at the sequence, structure and mechanism levels, different type IA enzymes do not participate in the same cellular processes. We have studied the mechanism of DNA relaxation by Escherichia coli topoisomerases I and III using single-molecule techniques to understand their dissimilarities. Our experiments show important differences at the single-molecule level, while also recovering the results from bulk experiments. Overall, topoisomerase III relaxes DNA using fast processive runs followed by long pauses, whereas topoisomerase I relaxes DNA through slow processive runs followed by short pauses. These two properties combined give rise to the overall relaxation rate, which is higher for topoisomerase I than for topoisomerase III, as expected from many biochemical observations. The results help us to understand better the role of these two topoisomerases in the cell and also serve to illustrate the power of single-molecule experiments to uncover new functional characteristics of biological molecules.

Synthesis and Characterisation of RuII Polypyridyl Complexes: DNA-Binding, Photocleavage, and Topoisomerase I and II Inhibitory Activity

2013 ◽  
Vol 66 (11) ◽  
pp. 1406 ◽  
Author(s):  
Xiaojun He ◽  
Guang Yang ◽  
Xiaonan Sun ◽  
Lingjun Xie ◽  
Lifeng Tan
Keyword(s):  
Dna Binding ◽  
Dna Cleavage ◽  
Topoisomerase I ◽  
Mixed Ligand ◽  
Dual Inhibitor ◽  
Cleavage Activity ◽  
Dna Cleavage Activity ◽  
Pbr322 Dna ◽  
Dna Strand ◽  
Strand Passage

Two mixed-ligand ruthenium(ii) complexes [Ru(phen)2(cptcp)]2+ (Ru1; phen = 1,10-phenanthroline, cptcp = 2-(4-carbazol-9-yl-phenyl)-1H-1,3,7,8-tetraaza-cyclopenta-[l]-phenanthrene) and [Ru(phen)2(btcpc)]2+ (Ru2; btcpc = 9-butyl-6-(1H-1,3,7,8-tetraaza-cyclo-cyclopenta-[l]-phenanthren-2-yl)-9H-carbazole-3-carbaldehyde) have been synthesised and characterised. The DNA-binding behaviours of the two complexes have been investigated by using spectroscopic and viscosity measurements. Results suggest that the two complexes bind to DNA by intercalation. The photocleavage of plasmid pBR322 DNA indicates that Ru1 exhibits more effective DNA cleavage activity in comparison to that exhibited by Ru2 under the same conditions, and different cleavage mechanisms are determined. Topoisomerase inhibition and DNA strand passage assay confirm that Ru1 may act as an efficient dual inhibitor of topoisomerases I and II, whereas Ru2 may only act as a single inhibitor of topoisomerases II.

scholarly journals DNA Topoisomerase III from the Hyperthermophilic Archaeon Sulfolobus solfataricus with Specific DNA Cleavage Activity

2003 ◽  
Vol 185 (18) ◽  
pp. 5500-5507 ◽  
Author(s):  
Penggao Dai ◽  
Ying Wang ◽  
Risheng Ye ◽  
Liang Chen ◽  
Li Huang
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase I ◽  
Sulfolobus Solfataricus ◽  
Dna Topoisomerase ◽  
Hyperthermophilic Archaeon ◽  
Dna Cleavage Activity ◽  
Topoisomerase Iii ◽  
Type Ia ◽  
Metal Cofactors ◽  
Dna Topoisomerase Iii

ABSTRACT We report the production, purification, and characterization of a type IA DNA topoisomerase, previously designated topoisomerase I, from the hyperthermophilic archaeon Sulfolobus solfataricus. The protein was capable of relaxing negatively supercoiled DNA at 75°C in the presence of Mg2+. Mutation of the putative active site Tyr318 to Phe318 led to the inactivation of the protein. The S. solfataricus enzyme cleaved oligonucleotides in a sequence-specific fashion. The cleavage occurred only in the presence of a divalent cation, preferably Mg2+. The cofactor requirement of the enzyme was partially satisfied by Cu2+, Co2+, Mn2+, Ca2+, or Ni2+. It appears that the enzyme is active with a broader spectrum of metal cofactors in DNA cleavage than in DNA relaxation (Mg2+ and Ca2+). The enzyme-catalyzed oligonucleotide cleavage required at least 7 bases upstream and 2 bases downstream of the cleavage site. Analysis of cleavage by the S. solfataricus enzyme on a set of oligonucleotides revealed a consensus cleavage sequence of the enzyme: 5′-G(A/T)CA(T)AG(T)G(A)X↓XX-3′. This sequence bears more resemblance to the preferred cleavage sites of topoisomerases III than to those of topoisomerases I. Based on these data and sequence analysis, we designate the enzyme S. solfataricus topoisomerase III.

Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

2013 ◽  
Author(s):  
Andrew M. Gulick ◽  
Thomas A. Russo ◽  
L. W. Schultz ◽  
Timothy C. Umland
Keyword(s):  
Drug Targets ◽  
Bacterial Infections ◽  
Drug Resistant ◽  
New Drug

scholarly journals Bloodstream infection with Acinetobacter baumanii in a Plasmodium falciparum positive infant: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Charity Wiafe Akenten ◽  
Kennedy Gyau Boahen ◽  
Kwadwo Sarfo Marfo ◽  
Nimako Sarpong ◽  
Denise Dekker ◽  
...  
Keyword(s):  
Case Report ◽  
Bacterial Infections ◽  
Treatment Options ◽  
Female Child ◽  
Correct Choice ◽  
Blood Cultures ◽  
Microbial Culture ◽  
Acinetobacter Baumanii ◽  
Inappropriate Use ◽  
History Of

Abstract Background The increasing incidence of multi-antibiotic-resistant bacterial infections, coupled with the risk of co-infections in malaria-endemic regions, complicates accurate diagnosis and prolongs hospitalization, thereby increasing the total cost of illness. Further, there are challenges in making the correct choice of antibiotic treatment and duration, precipitated by a lack of access to microbial culture facilities in many hospitals in Ghana. The aim of this case report is to highlight the need for blood cultures or alternative rapid tests to be performed routinely in malaria patients, to diagnose co-infections with bacteria, especially when symptoms persist after antimalarial treatment. Case presentation A 6-month old black female child presented to the Agogo Presbyterian Hospital with fever, diarrhea, and a 3-day history of cough. A rapid diagnostic test for malaria and Malaria microscopy was positive for P. falciparum with a parasitemia of 224 parasites/μl. The patient was treated with Intravenous Artesunate, parental antibiotics (cefuroxime and gentamicin) and oral dispersible zinc tablets in addition to intravenous fluids. Blood culture yielded Acinetobacter baumanii, which was resistant to all of the third-generation antibiotics included in the susceptibility test conducted, but sensitive to ciprofloxacin and gentamicin. After augmenting treatment with intravenous ciprofloxacin, all symptoms resolved. Conclusion Even though this study cannot confirm whether the bacterial infection was nosocomial or otherwise, the case highlights the necessity to test malaria patients for possible co-infections, especially when fever persists after parasites have been cleared from the bloodstream. Bacterial blood cultures and antimicrobial susceptibility testing should be routinely performed to guide treatment options for febril illnesses in Ghana in order to reduce inappropriate use of broad-spectrum antibiotics and limit the development of antimicrobial resistance.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

scholarly journals Mechanistic insights into the R-loop formation and cleavage in CRISPR-Cas12i1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bo Zhang ◽  
Diyin Luo ◽  
Yu Li ◽  
Vanja Perčulija ◽  
Jing Chen ◽  
...  
Keyword(s):  
Genome Editing ◽  
Dna Cleavage ◽  
Binary Complex ◽  
Loop Formation ◽  
Dna Duplex ◽  
Target Dna ◽  
Before And After ◽  
Dna Strand ◽  
Type V ◽  
Functionally Diverse

AbstractCas12i is a newly identified member of the functionally diverse type V CRISPR-Cas effectors. Although Cas12i has the potential to serve as genome-editing tool, its structural and functional characteristics need to be investigated in more detail before effective application. Here we report the crystal structures of the Cas12i1 R-loop complexes before and after target DNA cleavage to elucidate the mechanisms underlying target DNA duplex unwinding, R-loop formation and cis cleavage. The structure of the R-loop complex after target DNA cleavage also provides information regarding trans cleavage. Besides, we report a crystal structure of the Cas12i1 binary complex interacting with a pseudo target oligonucleotide, which mimics target interrogation. Upon target DNA duplex binding, the Cas12i1 PAM-interacting cleft undergoes a remarkable open-to-closed adjustment. Notably, a zipper motif in the Helical-I domain facilitates unzipping of the target DNA duplex. Formation of the 19-bp crRNA-target DNA strand heteroduplex in the R-loop complexes triggers a conformational rearrangement and unleashes the DNase activity. This study provides valuable insights for developing Cas12i1 into a reliable genome-editing tool.

scholarly journals Staring at the Naked Goddess: Unraveling the Structure and Reactivity of Artemis Endonuclease Interacting with a DNA Double Strand

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3986
Author(s):  
Cécilia Hognon ◽  
Antonio Monari
Keyword(s):  
Dna Cleavage ◽  
Catalytic Mechanism ◽  
Dna Lesions ◽  
Cleavage Reaction ◽  
Dynamic Simulations ◽  
Important Target ◽  
System Adaptation ◽  
Dna Strands ◽  
Dna Strand ◽  
Dna Substrate

Artemis is an endonuclease responsible for breaking hairpin DNA strands during immune system adaptation and maturation as well as the processing of potentially toxic DNA lesions. Thus, Artemis may be an important target in the development of anticancer therapy, both for the sensitization of radiotherapy and for immunotherapy. Despite its importance, its structure has been resolved only recently, and important questions concerning the arrangement of its active center, the interaction with the DNA substrate, and the catalytic mechanism remain unanswered. In this contribution, by performing extensive molecular dynamic simulations, both classically and at the hybrid quantum mechanics/molecular mechanics level, we evidenced the stable interaction modes of Artemis with a model DNA strand. We also analyzed the catalytic cycle providing the free energy profile and key transition states for the DNA cleavage reaction.

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