Anti-evolution Drugs: A New Paradigm to Combat Drug Resistance

2021 ◽  
Vol 18 ◽  
Author(s):  
Ramalingam Peraman ◽  
Santhivardhan Chinni ◽  
Sathish Kumar Sure ◽  
Vinay Kumar Kutagulla ◽  
Muthukumaran Peraman ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Analytical Techniques ◽  
New Drugs ◽  
New Paradigm ◽  
Rate Of Increase ◽  
Antibiotic Drug ◽  
Modern Genomic

: The drug resistance confronts chemotherapy of neoplasm and microbial infections. A vast array of molecular mechanisms was implicated in drug resistance, including, generation of drug efflux transporters, mutation of drug targets, and alteration of drug metabolism. With the alarming rate of increase in drug resistance, pathogens are bolstering in such a way that many new drugs face efficacy problems within a short span of entry into the market. Evolution is the driving force towards the development of drug resistance. By adopting the modern genomic and functionomic analytical techniques, scientists have now identified novel genes and signalling proteins involved in the evolution of drug resistance in microorganisms. Given the current knowledge of bacterial evolution, the antibiotic drug discovery is ready for a paradigm shift to explore the newer ways to tackle drug resistance. The article discusses such recent developments and reviews their merits and demerits in an attempt to envisage the findings in this new domain of medicine.

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

scholarly journals Identification of Biomolecules Involved in the Adaptation to the Environment of Cold-Loving Microorganisms and Metabolic Pathways for Their Production

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1155
Author(s):  
Eva Garcia-Lopez ◽  
Paula Alcazar ◽  
Cristina Cid
Keyword(s):  
Metabolic Pathways ◽  
Extracellular Polymeric Substances ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Analytical Techniques ◽  
Light Protection ◽  
Domains Of Life ◽  
Mechanisms Of Adaptation ◽  
Resistance To Stress ◽  
Function Discovery

Cold-loving microorganisms of all three domains of life have unique and special abilities that allow them to live in harsh environments. They have acquired structural and molecular mechanisms of adaptation to the cold that include the production of anti-freeze proteins, carbohydrate-based extracellular polymeric substances and lipids which serve as cryo- and osmoprotectants by maintaining the fluidity of their membranes. They also produce a wide diversity of pigmented molecules to obtain energy, carry out photosynthesis, increase their resistance to stress and provide them with ultraviolet light protection. Recently developed analytical techniques have been applied as high-throughoutput technologies for function discovery and for reconstructing functional networks in psychrophiles. Among them, omics deserve special mention, such as genomics, transcriptomics, proteomics, glycomics, lipidomics and metabolomics. These techniques have allowed the identification of microorganisms and the study of their biogeochemical activities. They have also made it possible to infer their metabolic capacities and identify the biomolecules that are parts of their structures or that they secrete into the environment, which can be useful in various fields of biotechnology. This Review summarizes current knowledge on psychrophiles as sources of biomolecules and the metabolic pathways for their production. New strategies and next-generation approaches are needed to increase the chances of discovering new biomolecules.

Computer-Aided Optimization of Combined Anti-Retroviral Therapy for HIV: New Drugs, New Drug Targets and Drug Resistance

2016 ◽  
Vol 14 (2) ◽  
pp. 101-109 ◽  
Author(s):  
Maurizio Zazzi ◽  
Alessandro Cozzi-Lepri ◽  
Mattia C.F. Prosperi
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
New Drugs ◽  
New Drug ◽  
Computer Aided

scholarly journals Efflux Pump Inhibitors against Nontuberculous Mycobacteria

2020 ◽  
Vol 21 (12) ◽  
pp. 4191
Author(s):  
Laura Rindi
Keyword(s):  
Drug Resistance ◽  
Efflux Pump ◽  
Nontuberculous Mycobacteria ◽  
Current Knowledge ◽  
New Drugs ◽  
Human Pathogens ◽  
Intracellular Accumulation ◽  
Promising Strategy ◽  
Combined Use ◽  
Efflux Pump Inhibitors

Over the last years, nontuberculous mycobacteria (NTM) have emerged as important human pathogens. Infections caused by NTM are often difficult to treat due to an intrinsic multidrug resistance for the presence of a lipid-rich outer membrane, thus encouraging an urgent need for the development of new drugs for the treatment of mycobacterial infections. Efflux pumps (EPs) are important elements that are involved in drug resistance by preventing intracellular accumulation of antibiotics. A promising strategy to decrease drug resistance is the inhibition of EP activity by EP inhibitors (EPIs), compounds that are able to increase the intracellular concentration of antimicrobials. Recently, attention has been focused on identifying EPIs in mycobacteria that could be used in combination with drugs. The aim of the present review is to provide an overview of the current knowledge on EPs and EPIs in NTM and also, the effect of potential EPIs as well as their combined use with antimycobacterial drugs in various NTM species are described.

scholarly journals Understanding the yeast host cell response to recombinant membrane protein production

2011 ◽  
Vol 39 (3) ◽  
pp. 719-723 ◽  
Author(s):  
Zharain Bawa ◽  
Charlotte E. Bland ◽  
Nicklas Bonander ◽  
Nagamani Bora ◽  
Stephanie P. Cartwright ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Drug Targets ◽  
Large Scale ◽  
Protein Production ◽  
Molecular Mechanisms ◽  
New Drugs ◽  
Host Cells ◽  
Host Cell Response ◽  
Wide Range

Membrane proteins are drug targets for a wide range of diseases. Having access to appropriate samples for further research underpins the pharmaceutical industry's strategy for developing new drugs. This is typically achieved by synthesizing a protein of interest in host cells that can be cultured on a large scale, allowing the isolation of the pure protein in quantities much higher than those found in the protein's native source. Yeast is a popular host as it is a eukaryote with similar synthetic machinery to that of the native human source cells of many proteins of interest, while also being quick, easy and cheap to grow and process. Even in these cells, the production of human membrane proteins can be plagued by low functional yields; we wish to understand why. We have identified molecular mechanisms and culture parameters underpinning high yields and have consolidated our findings to engineer improved yeast host strains. By relieving the bottlenecks to recombinant membrane protein production in yeast, we aim to contribute to the drug discovery pipeline, while providing insight into translational processes.

scholarly journals D-Amino Acids and D-Amino Acid-Containing Peptides: Potential Disease Biomarkers and Therapeutic Targets?

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1716
Author(s):  
Mohamed Abdulbagi ◽  
Liya Wang ◽  
Orwa Siddig ◽  
Bin Di ◽  
Bo Li
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Analytical Techniques ◽  
The Other ◽  
Disease Development ◽  
Disease Biomarkers ◽  
New Biomarkers ◽  
Structure Of Proteins

In nature, amino acids are found in two forms, L and D enantiomers, except for glycine which does not have a chiral center. The change of one form to the other will lead to a change in the primary structure of proteins and hence may affect the function and biological activity of proteins. Indeed, several D-amino acid-containing peptides (DAACPs) were isolated from patients with cataracts, Alzheimer’s and other diseases. Additionally, significant levels of free D-amino acids were found in several diseases, reflecting the disease conditions. Studying the molecular mechanisms of the DAACPs formation and the alteration in D-amino acids metabolism will certainly assist in understanding these diseases and finding new biomarkers and drug targets. In this review, the presence of DAACPs and free D-amino acids and their links with disease development and progress are summarized. Similarly, we highlight some recent advances in analytical techniques that led to improvement in the discovery and analysis of DAACPs and D-amino acids.

scholarly journals Mechanistic Insights of Drug Resistance in Staphylococcus Aureus with Special Reference to Newer Antibiotics

2021 ◽  
Author(s):  
Atamjit Singh ◽  
Kirandeep Kaur ◽  
Pallvi Mohana ◽  
Avneet Kaur ◽  
Komalpreet Kaur ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Resistance ◽  
Special Reference ◽  
Healthcare System ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Pathogenic Bacterium ◽  
Functional Behavior ◽  
Genetic Modifications ◽  
Shed Light

Staphylococcus aureus is the most ubiquitous microorganism in both environment as well as animals and exists as commensal and pathogenic bacterium. In past few years it has been emerged as a superbug causing serious burden on healthcare system. This bacterium has been found to be the most resistant one toward most of the antibiotics due to its rapid structural and genetic modifications. This chapter will shed light on various types of molecular mechanisms responsible for resistance of Staphylococcus aureus showcasing how it has been emerged as a superbug. Moreover, the recent approaches which include exploring of different drug targets keeping in view the structural and functional behavior of the Staphylococcus aureus has also been discussed.

Analysis of the differences in the Expression of mRNAs and miRNAs Asso-ciated with Drug Resistance in Endometrial Cancer Cells Treated with Salinomycin

2020 ◽  
Vol 21 ◽  
Author(s):  
Piotr Januszyk ◽  
Krzysztof Januszyk ◽  
Magdalena Wierzbik-Strońska ◽  
Dariusz Boroń ◽  
Beniamin Grabarek
Keyword(s):  
Drug Resistance ◽  
Endometrial Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Cell Line ◽  
Control Culture ◽  
New Drugs ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Expression Of Genes

Background: It is important to understand the molecular mechanisms involved in cancer drug resistance and to study the activity of new drugs, e.g. salinomycin. Objective: The purpose of the study was to analyze changes in the expression of genes associated with drug resistance in the Ishikawa endometrial cancer cell line when treated with salinomycin. In addition, changes in the level of miRNA potentially regulating these mRNAs were evaluated. Results: The following was observed about the number of mRNAs differentiating the cell culture exposed to the drug compared to a control culture: H-12 vs C - 9 mRNAs, H_24 vs C – 6 mRNAs, H_48 vs C - 1 mRNA. It was noted that 4 of the 9 differentiating mRNAs were characteristic for 12 hours of exposure to the salinomycin and they correspond to the following genes: TUFT1, ABCB1, MTMR11, MX2. After 24 hours, 2 mRNAs were characteristic for this time of incubation cells with salinomycin: TUFT1, MYD88 and after 48 hours, SLC30A5 could also be observed. The highest differences in expression were indicated for TUFT1, MTMR11, SLC30A5. The highest influence probability was determined between TUFT1 and hsamiR-3188 (FC + 2.48), MTMR11and has-miR-16 (FC -1.74), and between SLC30A5 and hsa-miR-30d (FC -2.01). Materials and Methods: Endometrial cancer cells were treated with 1 µM of salinomycin for 12, 24 and 48 hour periods. Untreated cells were a control culture. The molecular analysis consists of mRNA and miRNA microarray analysis and the RTqPCR technique. Conclusions: Salinomycin induces changes in the activity of mRNA and miRNA participating in drug resistance, however the observed changes in character are an expected result of anti-cancer treatment.

Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents

2019 ◽  
Vol 14 (2) ◽  
pp. 113-132 ◽  
Author(s):  
Elmira Ekinci ◽  
Sagar Rohondia ◽  
Raheel Khan ◽  
Qingping P. Dou
Keyword(s):  
Drug Resistance ◽  
Superoxide Dismutase ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Chronic Alcoholism ◽  
New Drugs ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Anti Cancer

Background:Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity.Objective:To summarize the anti-cancer effects of Disulfiram through a thorough patent review.Methods:This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy.Results:Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug.Conclusion:For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.

INTERACTION OF SOME ANTIBIOTICS WITH SEMIORGANIC IODINE ADDUCTS

2021 ◽  
pp. 45-51
Author(s):  
А.Б. ДЖУМАГАЗИЕВА ◽  
Е.Н. САХИПОВ ◽  
С. ТУРГАНБАЙ ◽  
Н.М. АТАГЕЛЬДИЕВА ◽  
У.М. ДАТХАЕВ ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Ir Spectroscopy ◽  
Wide Spectrum ◽  
Uv Spectroscopy ◽  
Dosage Forms ◽  
New Drugs ◽  
Iodine Molecule ◽  
Antimicrobial Effects ◽  
Antibiotic Drug

Лекарственная устойчивость к антибиотикам вызвала необходимость поиска новых лекарственных средств и лекарственных форм. Известно, что семиорганические аддукты иода обладают широким спектром антимикробного действия. Эти же соединения, содержащие в своем составе молекулу галогена - иода, могут выступать в качестве галогенирующего агента в отношении антибиотиков. Изучено взаимодействие антибиотиков тетрациклина, гентамицина, хлорамфеникола, относящихся к классам поликетидов, аминогликозидов и амфениколов, соответственно, с аддуктом иода методами рефрактометрии, УФ-спектроскопии и ИК-спектроскопии. Показано, что антибиотик хлорамфеникол не взаимодействует с семиорганическим аддуктом иода ди2-аминопропионовой кислоты дитрииодоводород моногидратом (субстанция D1). Antibiotic drug resistance has necessitated the search for new drugs and dosage forms. It is known that semiorganic iodine adducts have a wide spectrum of antimicrobial effects. The same compounds containing a halogen-iodine molecule may act as a antibiotics halogenating agent. The interaction of antibiotics tetracycline, gentamicin, chloramphenicol belonging to the classes of polyketides, aminoglycosides and amphenicols, respectively, with iodine adduct by refractometry, UV spectroscopy and IR spectroscopy was studied. It has been shown that the antibiotic chloramphenicol does not interact with the semiorganic adduct of di-2-aminopropionic acid ditriiodinehydride monohydrate (D1 substance).

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