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Cureus Feb 2024Fluoroquinolones, a popular antibiotic class that inhibits nucleic acid synthesis of bacteria by disrupting the activity of the enzyme's topoisomerase IV and DNA gyrase,... (Review)
Review
Fluoroquinolones, a popular antibiotic class that inhibits nucleic acid synthesis of bacteria by disrupting the activity of the enzyme's topoisomerase IV and DNA gyrase, are used to treat bacterial infections. However, the widespread use of these drugs has allowed for the development of microbial resistance in recent years. Quinolones also have many clinically relevant side effects, including psychosis, confusion, seizures, headaches, dizziness, and nausea. Common side effects include tendinitis, myopathy, depression, and fatigue. Cardiovascular side effects include increased risk of aortic aneurysm, aortic dissection, and QT interval prolongation. Overall, quinolones can be an effective choice for treating bacterial infections. Still, the side effect profile and decreased efficacy secondary to microbial resistance no longer make the quinolone class an ideal choice for many types of infection. A better understanding of the role of quinolone-mediated or neurological damage, cardiovascular impairment, and musculoskeletal involvement is imperative to determine the risks/benefits for the clinician.
PubMed: 38516474
DOI: 10.7759/cureus.54565 -
Antibiotics (Basel, Switzerland) Nov 2021Quinolone resistance in bacterial pathogens has primarily been associated with mutations in the quinolone resistance-determining regions (QRDRs) of bacterial type-II... (Review)
Review
Quinolone resistance in bacterial pathogens has primarily been associated with mutations in the quinolone resistance-determining regions (QRDRs) of bacterial type-II topoisomerases, which are DNA gyrase and topoisomerase IV. Depending on the position and type of the mutation (s) in the QRDRs, bacteria either become partially or completely resistant to quinolone. QRDR mutations have been identified and characterized in isolates from around the globe, particularly during the last decade, and efforts have been made to understand the propensity of different serovars to carry such mutations. Because there is currently no thorough analysis of the available literature on QRDR mutations in different serovars, this review aims to provide a comprehensive picture of the mutational diversity in QRDRs of serovars, summarizing the literature related to both typhoidal and non-typhoidal serovars with a special emphasis on recent findings. This review will also discuss plasmid-mediated quinolone-resistance determinants with respect to their additive or synergistic contributions with QRDR mutations in imparting elevated quinolone resistance. Finally, the review will assess the contribution of membrane transporter-mediated quinolone efflux to quinolone resistance in strains carrying QRDR mutations. This information should be helpful to guide the routine surveillance of foodborne serovars, especially with respect to their spread across countries, as well as to improve laboratory diagnosis of quinolone-resistant strains.
PubMed: 34943668
DOI: 10.3390/antibiotics10121455 -
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 -
Antimicrobial Agents and Chemotherapy Oct 2023Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial...
Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of antibacterial agents with a unique binding mode and distinct pharmacology that enables them to evade existing resistance mechanisms. The clinical development of NBTIs has been plagued by several issues, including cardiovascular safety. Herein, we report a sub-series of tricyclic NBTIs bearing an amide linkage that displays promising antibacterial activity, potent dual-target inhibition of DNA gyrase and topoisomerase IV (TopoIV), as well as improved cardiovascular safety and metabolic profiles. These amide NBTIs induced both single- and double-strand breaks in pBR322 DNA mediated by DNA gyrase, in contrast to prototypical NBTIs that cause only single-strand breaks. Unexpectedly, amides and targeted human topoisomerase IIα (TOP2α) causing both single- and double-strand breaks in pBR322 DNA, and induced DNA strand breaks in intact human leukemia K562 cells. In addition, anticancer drug-resistant K/VP.5 cells containing decreased levels of TOP2α were cross-resistant to amides and . Together, these results demonstrate broad spectrum antibacterial properties of selected tricyclic NBTIs, desirable safety profiles, an unusual ability to induce DNA double-stranded breaks, and activity against human TOP2α. Future work will be directed toward optimization and development of tricyclic NBTIs with potent and selective activity against bacteria. Finally, the current results may provide an additional avenue for development of selective anticancer agents.
Topics: Humans; Topoisomerase Inhibitors; DNA Gyrase; DNA Topoisomerase IV; Anti-Bacterial Agents; Staphylococcus aureus; DNA; Amides; Topoisomerase II Inhibitors; Microbial Sensitivity Tests
PubMed: 37724886
DOI: 10.1128/aac.00482-23 -
Nature Chemical Biology Nov 2022The antimicrobial resistance crisis requires the introduction of novel antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target...
The antimicrobial resistance crisis requires the introduction of novel antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target pathogens and harms the microbiome. This is especially true for Mycobacterium tuberculosis, where treatment requires a 6-month course of antibiotics. Here we show that a novel antimicrobial from Photorhabdus noenieputensis, which we named evybactin, is a potent and selective antibiotic acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site overlapping with synthetic thiophene poisons. Given the conserved nature of DNA gyrase, the observed selectivity against M. tuberculosis is puzzling. We found that evybactin is smuggled into the cell by a promiscuous transporter of hydrophilic compounds, BacA. Evybactin is the first, but likely not the only, antimicrobial compound found to employ this unusual mechanism of selectivity.
Topics: Humans; Topoisomerase II Inhibitors; Mycobacterium tuberculosis; DNA Gyrase; Anti-Bacterial Agents; Tuberculosis; Thiophenes; Poisons; Antitubercular Agents
PubMed: 35996001
DOI: 10.1038/s41589-022-01102-7 -
Antimicrobial Agents and Chemotherapy May 2021The worldwide distribution of genes found on plasmids and their presence on the chromosomes of aquatic bacteria, such as , one of the suspected sources, suggests an...
The worldwide distribution of genes found on plasmids and their presence on the chromosomes of aquatic bacteria, such as , one of the suspected sources, suggests an origin before the development of synthetic quinolones. However, their native function remains unknown. Previous work indicated that expression of in was induced by cold shock. To investigate its role further, we constructed single in-frame deletion mutants in and (the gene for cold shock protein) and a double mutant in and in ATCC 17562 to evaluate the response to different environmental conditions and stresses and to exposure to various DNA-damaging agents. We found that is involved in resistance to ciprofloxacin, levofloxacin, and mitomycin C and in the cold shock response in Moreover, Δ and Δ mutants showed slower growth when they were treated with bile salts at 37°C and then shifted to 15°C (cold shock) without bile salts in the medium, with the effect being stronger in the double mutant. This transition may mimic what happens when is ingested into the gastrointestinal tract and released in its natural environment. Cold shock and bile salts induced the expression of and DNA gyrase and topoisomerase IV genes. However, no induction was found in the Δ mutant, suggesting that the gene is involved in the response to DNA damage and nucleic acid secondary structure.
Topics: Bacterial Proteins; Ciprofloxacin; DNA Gyrase; DNA Topoisomerase IV; Quinolones; Vibrio vulnificus
PubMed: 33782008
DOI: 10.1128/AAC.00232-21 -
Pharmaceutics May 2021Flavonoids are among the most abundant natural bioactive compounds produced by plants. Many different activities have been reported for these secondary metabolites... (Review)
Review
Flavonoids are among the most abundant natural bioactive compounds produced by plants. Many different activities have been reported for these secondary metabolites against numerous cells and systems. One of the most interesting is certainly the antimicrobial, which is stimulated through various molecular mechanisms. In fact, flavonoids are effective both in directly damaging the envelope of Gram-negative and Gram-positive bacteria but also by acting toward specific molecular targets essential for the survival of these microorganisms. The purpose of this paper is to present an overview of the most interesting results obtained in the research focused on the study of the interactions between flavonoids and bacterial proteins. Despite the great structural heterogeneity of these plant metabolites, it is interesting to observe that many flavonoids affect the same cellular pathways. Furthermore, it is evident that some of these compounds interact with more than one target, producing multiple effects. Taken together, the reported data demonstrate the great potential of flavonoids in developing innovative systems, which can help address the increasingly serious problem of antibiotic resistance.
PubMed: 34062983
DOI: 10.3390/pharmaceutics13050660 -
Journal of Bacteriology Aug 2021Topoisomerase I (Topo I) of Escherichia coli, encoded by , acts to relax negative supercoils in DNA. Topo I deficiency results in hypernegative supercoiling, formation...
Topoisomerase I (Topo I) of Escherichia coli, encoded by , acts to relax negative supercoils in DNA. Topo I deficiency results in hypernegative supercoiling, formation of transcription-associated RNA-DNA hybrids (R-loops), and DnaA- and -independent constitutive stable DNA replication (cSDR), but some uncertainty persists as to whether is essential for viability in E. coli and related enterobacteria. Here, we show that several alleles, including Δ, confer lethality in derivatives of wild-type E. coli strain MG1655. Viability in the absence of Topo I was restored with two perturbations, neither of which reversed the hypernegative supercoiling phenotype: (i) in a reduced-genome strain (MDS42) or (ii) by an RNA polymerase (RNAP) mutation, , that has been reported to alleviate the deleterious consequences of RNAP backtracking and transcription-replication conflicts. Four phenotypes related to cSDR were identified for mutants: (i) one of the alleles rescued Δ lethality; (ii) in derivatives, Topo I deficiency generated a characteristic copy number peak in the terminus region of the chromosome; (iii) was synthetically lethal with (encoding RNase HI, whose deficiency also confers cSDR); and (iv) synthetic lethality was itself rescued by Δ. We propose that the terminal lethal consequence of hypernegative DNA supercoiling in E. coli mutants is RNAP backtracking during transcription elongation and associated R-loop formation, which in turn leads to transcription-replication conflicts and to cSDR. In all life forms, double-helical DNA exists in a topologically supercoiled state. The enzymes DNA gyrase and topoisomerase I act, respectively, to introduce and to relax negative DNA supercoils in Escherichia coli. That gyrase deficiency leads to bacterial death is well established, but the essentiality of topoisomerase I for viability has been less certain. This study confirms that topoisomerase I is essential for E. coli viability and suggests that in its absence, aberrant chromosomal DNA replication and excessive transcription-replication conflicts occur that are responsible for lethality.
Topics: Bacterial Proteins; Chromosomes, Bacterial; DNA Replication; DNA Topoisomerases, Type I; DNA, Bacterial; DNA-Binding Proteins; Escherichia coli; Genome, Bacterial; Transcription, Genetic
PubMed: 34124945
DOI: 10.1128/JB.00195-21 -
Journal of Infection and Chemotherapy :... Apr 2020Mycobacterium leprae causes leprosy and ofloxacin is used to control this bacterium. However, specific amino acid substitutions in DNA gyrases of M. leprae interferes...
BACKGROUND
Mycobacterium leprae causes leprosy and ofloxacin is used to control this bacterium. However, specific amino acid substitutions in DNA gyrases of M. leprae interferes with the effect of ofloxacin.
METHODOLOGY/PRINCIPAL FINDINGS
Here we tested the inhibitory effect of WQ-3810 on DNA gyrases in M. leprae, using recombinant gyrases. We theorized that WQ-3810 and DNA gyrases interacted, which was tested in silico. Compared with control drugs like ofloxacin, WQ-3810 showed a better inhibitory effect on ofloxacin-resistant DNA gyrases. The in-silico study showed that, unlike control drugs, a specific linkage between a R1 group in WQ-3810 and aspartic acid at position 464 in the subunit B of DNA gyrases existed, which would enhance the inhibitory effect of WQ-3810. This linkage was confirmed in a further experiment, using recombinant DNA gyrases with amino acid substitutions in subunits B instead.
CONCLUSIONS/SIGNIFICANCE
The inhibitory effect of WQ-3810 was likely enhanced by the specific linkage between a R1 group residue in its structure and DNA gyrases. Using interactions like the one found in the present work may help design new fluoroquinolones that contribute to halt the emergence of antibiotic-resistant pathogens.
Topics: Anti-Bacterial Agents; Azetidines; DNA Gyrase; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Leprosy; Microbial Sensitivity Tests; Mycobacterium leprae; Ofloxacin
PubMed: 31839561
DOI: 10.1016/j.jiac.2019.10.013 -
Antimicrobial Agents and Chemotherapy May 2023Bacterial type II topoisomerases, DNA gyrase and topoisomerase IV, are targets of many antibiotics including fluoroquinolones (FQs). Unfortunately, a number of bacterial...
Bacterial type II topoisomerases, DNA gyrase and topoisomerase IV, are targets of many antibiotics including fluoroquinolones (FQs). Unfortunately, a number of bacterial species easily acquire resistance to FQs by mutations in either DNA gyrase or topoisomerase IV genes. The emergence of resistant pathogenic strains is a global problem in healthcare, therefore, identifying alternative pathways to thwart their persistence is the current frontier in drug discovery. An attractive class of compounds is nybomycins, reported to be "reverse antibiotics" that selectively inhibit growth of some Gram-positive FQ-resistant bacteria by targeting the mutant form of DNA gyrase, while being inactive against wild-type strains with FQ-sensitive gyrases. The strong "reverse" effect was demonstrated only for a few Gram-positive organisms resistant to FQs due to the S83L/I mutation in GyrA subunit of DNA gyrase. However, the activity of nybomycins has not been extensively explored among Gram-negative species. Here, we observed that in Gram-negative ΔtolC strain with enhanced permeability, wild-type gyrase and GyrA S83L mutant, resistant to fluoroquinolones, are both similarly sensitive to nybomycin.
PubMed: 33593838
DOI: 10.1128/AAC.00777-20