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Antibiotics (Basel, Switzerland) Apr 2024, (GAS), and (GBS) are bacteria that can cause a range of infections, some of them life-threatening. This review examines the spread of antibiotic resistance and its... (Review)
Review
, (GAS), and (GBS) are bacteria that can cause a range of infections, some of them life-threatening. This review examines the spread of antibiotic resistance and its mechanisms against antibiotics for streptococcal infections. Data on high-level penicillin-resistant invasive pneumococci have been found in Brazil (42.8%) and Japan (77%). The resistance is caused by mutations in genes that encode penicillin-binding proteins. Similarly, GAS and GBS strains reported from Asia, the USA, and Africa have undergone similar transformations in PBPs. Resistance to major alternatives of penicillins, macrolides, and lincosamides has become widespread among pneumococci and streptococci, especially in Asia (70-95%). The combination of several types with (B) is associated with the development of high-level macrolide resistance in GAS. Major mechanisms are ribosomal target modifications encoded by genes, ribosomal alterations, and active efflux pumps that regulate antibiotic entry due to A/E and D genes. Tetracycline resistance for streptococci in different countries varied from 22.4% in the USA to 83.7/100% in China, due to genes. Combined tetracycline/macrolide resistance is usually linked with the insertion of into the transposon carrying . New quinolone resistance is increasing by between 11.5 and 47.9% in Asia and Europe. The mechanism of quinolone resistance is based on mutations in /, determinants for DNA gyrase, or / encoding topoisomerase IV. The results for antibiotic resistance are alarming, and urgently call for increased monitoring of this problem and precautionary measures for control to prevent the spread of resistant mutant strains.
PubMed: 38667036
DOI: 10.3390/antibiotics13040360 -
International Journal of Molecular... Mar 2024With the rapid emergence of drug-resistant strains of (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently,...
With the rapid emergence of drug-resistant strains of (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as a potential anti-TB target, with novobiocin and SPR719 proposed as inhibitors targeting GyrB. Therefore, elucidating the molecular interactions between GyrB and its inhibitors is crucial for the discovery and design of efficient GyrB inhibitors for combating multidrug-resistant TB. In this study, we revealed the detailed binding mechanisms and dissociation processes of the representative inhibitors, novobiocin and SPR719, with GyrB using classical molecular dynamics (MD) simulations, tau-random acceleration molecular dynamics (τ-RAMD) simulations, and steered molecular dynamics (SMD) simulations. Our simulation results demonstrate that both electrostatic and van der Waals interactions contribute favorably to the inhibitors' binding to GyrB, with Asn52, Asp79, Arg82, Lys108, Tyr114, and Arg141 being key residues for the inhibitors' attachment to GyrB. The τ-RAMD simulations indicate that the inhibitors primarily dissociate from the ATP channel. The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors.
Topics: Mycobacterium tuberculosis; Novobiocin; Thermodynamics; Antitubercular Agents; Molecular Dynamics Simulation; Adenosine Triphosphate
PubMed: 38612573
DOI: 10.3390/ijms25073764 -
Molecules (Basel, Switzerland) Mar 2024Carbothioamides , were generated in high yield by reacting furan imidazolyl ketone with -arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The...
Carbothioamides , were generated in high yield by reacting furan imidazolyl ketone with -arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The reaction of carbothioamides , with hydrazonyl chlorides - in EtOH with triethylamine at reflux produced 1,3-thiazole derivatives -. In a different approach, the 1,3-thiazole derivatives and were produced by reacting and with chloroacetone to afford and , respectively, followed by diazotization with 4-methylbenzenediazonium chloride. The thiourea derivatives and then reacted with ethyl chloroacetate in ethanol with AcONa at reflux to give the thiazolidinone derivatives and . The produced compounds were tested for antioxidant and antibacterial properties. Using phosphomolybdate, promising thiazoles and showed the best antioxidant activities at 1962.48 and 2007.67 µgAAE/g dry samples, respectively. Thiazoles and had the highest antibacterial activity against and with 28, 25 and 27, 28 mm, respectively. Thiazoles and had the best activity against with 26 mm and 37 mm, respectively. Thiazole had the highest activity against , surpassing cyclohexamide. Most compounds demonstrated lower MIC values than neomycin against , and . A molecular docking study examined how antimicrobial compounds interact with DNA gyrase B crystal structures. The study found that all of the compounds had good binding energy to the enzymes and reacted similarly to the native inhibitor with the target DNA gyrase B enzymes' key amino acids.
Topics: Antioxidants; Molecular Docking Simulation; DNA Gyrase; Escherichia coli; Staphylococcus aureus; Anti-Bacterial Agents; Imidazoles; Candida albicans; Thiazoles
PubMed: 38611769
DOI: 10.3390/molecules29071491 -
ACS Infectious Diseases Apr 2024Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical...
Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical issue. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial in clinical development. Recently, phase III clinical trials for gepotidacin treatment of uncomplicated urinary tract infections caused by uropathogens, including , were stopped for demonstrated efficacy. Because of the clinical promise of gepotidacin, it is important to understand how the compound interacts with its cellular targets, gyrase and topoisomerase IV, from . Consequently, we determined how gyrase and topoisomerase IV mutations in amino acid residues that are involved in gepotidacin interactions affect the susceptibility of cells to the compound and characterized the effects of gepotidacin on the activities of purified wild-type and mutant gyrase and topoisomerase IV. Gepotidacin displayed well-balanced dual-targeting of gyrase and topoisomerase IV in cells, which was reflected in a similar inhibition of the catalytic activities of these enzymes by the compound. Gepotidacin induced gyrase/topoisomerase IV-mediated single-stranded, but not double-stranded, DNA breaks. Mutations in GyrA and ParC amino acid residues that interact with gepotidacin altered the activity of the compound against the enzymes and, when present in both gyrase and topoisomerase IV, reduced the antibacterial activity of gepotidacin against this mutant strain. Our studies provide insights regarding the well-balanced dual-targeting of gyrase and topoisomerase IV by gepotidacin in .
Topics: Acenaphthenes; Amino Acids; Anti-Bacterial Agents; DNA Gyrase; DNA Topoisomerase IV; Escherichia coli; Heterocyclic Compounds, 3-Ring
PubMed: 38606465
DOI: 10.1021/acsinfecdis.3c00346 -
ACS Infectious Diseases Apr 2024Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been...
Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been curtailed by target-mediated resistance, which is caused by mutations in the fluoroquinolone targets, gyrase and topoisomerase IV. An important pathogen that has been affected by this resistance is , the causative agent of gonorrhea. Over 82 million new cases of this sexually transmitted infection were reported globally in 2020. Despite the impact of fluoroquinolone resistance on gonorrhea treatment, little is known about the interactions of this drug class with its targets in this bacterium. Therefore, we investigated the effects of the fluoroquinolone ciprofloxacin on the catalytic and DNA cleavage activities of wild-type gyrase and topoisomerase IV and the corresponding enzymes that harbor mutations associated with cellular and clinical resistance to fluoroquinolones. Results indicate that ciprofloxacin interacts with both gyrase (its primary target) and topoisomerase IV (its secondary target) through a water-metal ion bridge that has been described in other species. Moreover, mutations in amino acid residues that anchor this bridge diminish the susceptibility of the enzymes for the drug, leading to fluoroquinolone resistance. Results further suggest that ciprofloxacin primarily induces its cytotoxic effects by enhancing gyrase-mediated DNA cleavage as opposed to inhibiting the DNA supercoiling activity of the enzyme. In conclusion, this work links the effects of ciprofloxacin on wild-type and resistant gyrase to results reported for cellular and clinical studies and provides a mechanistic explanation for the targeting and resistance of fluoroquinolones in .
Topics: Humans; Ciprofloxacin; Fluoroquinolones; DNA Topoisomerase IV; Neisseria gonorrhoeae; Gonorrhea; DNA Gyrase; Microbial Sensitivity Tests
PubMed: 38606464
DOI: 10.1021/acsinfecdis.4c00041 -
Science (New York, N.Y.) Apr 2024DNA supercoiling must be precisely regulated by topoisomerases to prevent DNA entanglement. The interaction of type IIA DNA topoisomerases with two DNA molecules,...
DNA supercoiling must be precisely regulated by topoisomerases to prevent DNA entanglement. The interaction of type IIA DNA topoisomerases with two DNA molecules, enabling the transport of one duplex through the transient double-stranded break of the other, remains elusive owing to structures derived solely from single linear duplex DNAs lacking topological constraints. Using cryo-electron microscopy, we solved the structure of DNA gyrase bound to a negatively supercoiled minicircle DNA. We show how DNA gyrase captures a DNA crossover, revealing both conserved molecular grooves that accommodate the DNA helices. Together with molecular tweezer experiments, the structure shows that the DNA crossover is of positive chirality, reconciling the binding step of gyrase-mediated DNA relaxation and supercoiling in a single structure.
Topics: Cryoelectron Microscopy; DNA; DNA Gyrase; DNA, Superhelical; Escherichia coli; Escherichia coli Proteins; Protein Domains
PubMed: 38603484
DOI: 10.1126/science.adl5899 -
Cell Reports Apr 2024In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a...
In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a small fraction of these, however, are characterized with respect to mechanism of action (MOA). Here, we describe a pipeline that categorizes transcriptional responses to antibiotics and provides hypotheses for MOA. 3D-printed imaging hardware PFIboxes) profiles responses of Escherichia coli promoter-GFP fusions to more than 100 antibiotics. Notably, metergoline, a semi-synthetic ergot alkaloid, mimics a DNA replication inhibitor. In vitro supercoiling assays confirm this prediction, and a potent analog thereof (MLEB-1934) inhibits growth at 0.25 μg/mL and is highly active against quinolone-resistant strains of methicillin-resistant Staphylococcus aureus. Spontaneous suppressor mutants map to a seldom explored allosteric binding pocket, suggesting a mechanism distinct from DNA gyrase inhibitors used in the clinic. In all, the work highlights the potential of this platform to rapidly assess MOA of new antibacterial compounds.
Topics: Topoisomerase II Inhibitors; DNA Gyrase; Anti-Bacterial Agents; Escherichia coli; Transcription, Genetic; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests
PubMed: 38578824
DOI: 10.1016/j.celrep.2024.114053 -
ACS Infectious Diseases Apr 2024Beyond their requisite functions in many critical DNA processes, the bacterial type II topoisomerases, gyrase and topoisomerase IV, are the targets of fluoroquinolone... (Review)
Review
Beyond their requisite functions in many critical DNA processes, the bacterial type II topoisomerases, gyrase and topoisomerase IV, are the targets of fluoroquinolone antibacterials. These drugs act by stabilizing gyrase/topoisomerase IV-generated DNA strand breaks and by robbing the cell of the catalytic activities of these essential enzymes. Since their clinical approval in the mid-1980s, fluoroquinolones have been used to treat a broad spectrum of infectious diseases and are listed among the five "highest priority" critically important antimicrobial classes by the World Health Organization. Unfortunately, the widespread use of fluoroquinolones has been accompanied by a rise in target-mediated resistance caused by specific mutations in gyrase and topoisomerase IV, which has curtailed the medical efficacy of this drug class. As a result, efforts are underway to identify novel antibacterials that target the bacterial type II topoisomerases. Several new classes of gyrase/topoisomerase IV-targeted antibacterials have emerged, including novel bacterial topoisomerase inhibitors, gyrase inhibitors, triazaacenaphthylenes, spiropyrimidinetriones, and thiophenes. Phase III clinical trials that utilized two members of these classes, gepotidacin (triazaacenaphthylene) and zoliflodacin (spiropyrimidinetrione), have been completed with positive outcomes, underscoring the potential of these compounds to become the first new classes of antibacterials introduced into the clinic in decades. Because gyrase and topoisomerase IV are validated targets for established and emerging antibacterials, this review will describe the catalytic mechanism and cellular activities of the bacterial type II topoisomerases, their interactions with fluoroquinolones, the mechanism of target-mediated fluoroquinolone resistance, and the actions of novel antibacterials against wild-type and fluoroquinolone-resistant gyrase and topoisomerase IV.
Topics: DNA Topoisomerase IV; Fluoroquinolones; DNA Gyrase; Topoisomerase II Inhibitors; Anti-Bacterial Agents; DNA; Mycobacterium tuberculosis
PubMed: 38564341
DOI: 10.1021/acsinfecdis.4c00128 -
Advances in Pharmacological and... 2024is one of the traditional medicinal plants used in Ethiopia to treat different ailments, such as cancer and diseases related to the respiratory system. This study aimed...
is one of the traditional medicinal plants used in Ethiopia to treat different ailments, such as cancer and diseases related to the respiratory system. This study aimed to isolate the phytochemical components of the root of and evaluate their and biological activities. Oleic acid (1), palmitic acid (2), sterols (3 and 4), boehmenan (5), and carolignans E (6 and 7) were isolated by silica gel column chromatography and preparative thin layer chromatography and characterized by NMR spectroscopy. Compounds 5-7 were isolated from the plant for the first time. At 5 mg/mL, the inhibition zone of evaluated compounds ranged from 8.80 to 11.10 mm against all selected bacteria. The MIC of the MeOH and -hexane: EtOAc (1 : 1) extracts was greater than or equal to 50 mg/mL against all selected bacteria. At 62.5 g/mL, the % DPPH radical scavenging activity of tested compounds ranged from 30.3% to 92.1% with an IC value of 19.4 to 2.1 g/mL. The results of molecular docking studies indicated that the docking scores of compounds 3-7 ranged from -6.4 to -7.9 kcal/mol against DNA gyrase B, -8.3 to -9.0 kcal/mol against the quinolone signal A, -7.1 to -8.5 kcal/mol against pyruvate kinase M2, and -7.9 to -8.5 kcal/mol against human topoisomerase . The results of the antibacterial activity of compounds , , and supported the antibacterial test results. Compound had a better docking score against human topoisomerase than the other test samples demonstrating its potential as an anticancer agent. Therefore, compounds 3-7 could be considered as a lead for developing antibacterial and anticancer drugs. Moreover, the presence of these active phytochemicals supports the traditional use of this plant against cancer and bacteria.
PubMed: 38562543
DOI: 10.1155/2024/3152929 -
Nature Communications Mar 2024In all living cells, genomic DNA is compacted through interactions with dedicated proteins and/or the formation of plectonemic coils. In bacteria, DNA compaction is...
In all living cells, genomic DNA is compacted through interactions with dedicated proteins and/or the formation of plectonemic coils. In bacteria, DNA compaction is achieved dynamically, coordinated with dense and constantly changing transcriptional activity. H-NS, a major bacterial nucleoid structuring protein, is of special interest due to its interplay with RNA polymerase. H-NS:DNA nucleoprotein filaments inhibit transcription initiation by RNA polymerase. However, the discovery that genes silenced by H-NS can be activated by transcription originating from neighboring regions has suggested that elongating RNA polymerases can disassemble H-NS:DNA filaments. In this study, we present evidence that transcription-induced counter-silencing does not require transcription to reach the silenced gene; rather, it exerts its effect at a distance. Counter-silencing is suppressed by introducing a DNA gyrase binding site within the intervening segment, suggesting that the long-range effect results from transcription-driven positive DNA supercoils diffusing toward the silenced gene. We propose a model wherein H-NS:DNA complexes form in vivo on negatively supercoiled DNA, with H-NS bridging the two arms of the plectoneme. Rotational diffusion of positive supercoils generated by neighboring transcription will cause the H-NS-bound negatively-supercoiled plectoneme to "unroll" disrupting the H-NS bridges and releasing H-NS.
Topics: Chromatin; DNA-Binding Proteins; Bacterial Proteins; Bacteria; DNA-Directed RNA Polymerases; DNA; Gene Silencing; Gene Expression Regulation, Bacterial; DNA, Bacterial; Transcription, Genetic
PubMed: 38555352
DOI: 10.1038/s41467-024-47114-w