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Journal of Inorganic Biochemistry Dec 2023Nalidixic acid (NAL) is a broad-spectrum antimicrobial widely used for urinary tract infections. As demonstrated, complexation of NAL with Zn, Mn and Cu was often used...
Nalidixic acid (NAL) is a broad-spectrum antimicrobial widely used for urinary tract infections. As demonstrated, complexation of NAL with Zn, Mn and Cu was often used to get new formulations with an enhanced efficiency and potency. Therefore, the elucidation of behavior of NAL in solution and of its interaction with metal cations are crucial to better understand the influence of complexation on NAL efficiency and to find the optimal conditions to propose novel formulations. As a preliminary study, spectrophotometric titrations were carried out on NAL to determine the values of the protonation constants and to define its acid-base behavior. Then, the interaction with the three metal cations Zn, Mn and Cu was investigated by potentiometric and spectrophotometric titrations, varying the conditions of temperature, ionic strength and metal-ligand ratio, thus allowing to get the most robust speciation model and to determine the formation constants with Zn, Mn, and Cu under different conditions, the sequestering ability of NAL towards metal cations, the formation enthalpic and entropic changes. A simulation under serum conditions was reported to show the relevance of the investigated species. Finally, LD-MS (laser desorption ionization mass spectrometry) and MS/MS analyses highlighted for all systems the formation of the complex species between Zn, Mn and Cu with NAL. MS/MS investigations assigned the sites of coordination of the ligand with the metal cation. More precisely, deprotonated NAL coordinates the metal cation via the oxygens of the carboxylate and the carbonyl groups.
Topics: Nalidixic Acid; Tandem Mass Spectrometry; Ligands; Metals; Cations; Water
PubMed: 37734219
DOI: 10.1016/j.jinorgbio.2023.112366 -
Canadian Medical Association Journal Oct 1972
Topics: Acute Kidney Injury; Adult; Bacteria; Drug Hypersensitivity; Drug Resistance, Microbial; Female; Humans; Nalidixic Acid; Neuralgia; Pyelonephritis; Rheumatic Diseases; Urinary Tract Infections
PubMed: 4541768
DOI: No ID Found -
Journal of Clinical Pharmacology Sep 2016Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of... (Review)
Review
Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of distribution, and a broad spectrum of antimicrobial activity. Despite their attractive profile as anti-infective agents, their use in children is limited, primarily due to safety concerns. In this review we highlight the pharmacological properties of fluoroquinolones and describe their current use in pediatrics. In addition, we provide a comprehensive assessment of the safety data associated with fluoroquinolone use in children. Although permanent or destructive arthropathy remains a significant concern, currently available data demonstrate that arthralgia and arthropathy are relatively uncommon in children and resolve following cessation of fluoroquinolone exposure without resulting in long-term sequelae. The concern for safety and risk of adverse events associated with pediatric fluoroquinolone use is likely driving the limited prescribing of this drug class in pediatrics. However, in adults, fluoroquinolones are the most commonly prescribed broad-spectrum antibiotics, resulting in the development of drug-resistant bacteria that can be challenging to treat effectively. The consequence of misuse and overuse of fluoroquinolones leading to drug resistance is a greater, but frequently overlooked, safety concern that applies to both children and adults and one that should be considered at the point of prescribing.
Topics: Age Factors; Animals; Anti-Bacterial Agents; Child; Clinical Trials as Topic; DNA Gyrase; Drug Resistance, Bacterial; Fluoroquinolones; Gastrointestinal Diseases; Humans; Nalidixic Acid; Prospective Studies; Retrospective Studies; Topoisomerase II Inhibitors
PubMed: 26865283
DOI: 10.1002/jcph.715 -
British Medical Journal Jun 1968
Topics: Anti-Infective Agents, Urinary; Escherichia coli Infections; Humans; Hydrogen-Ion Concentration; Mandelic Acids; Methenamine; Nalidixic Acid; Nitrofurantoin; Proteus Infections; Urine
PubMed: 4872850
DOI: No ID Found -
MSphere Feb 2021Horizontal gene transfer is a significant driver of evolutionary dynamics across microbial populations. Although the benefits of the acquisition of new genetic material...
Horizontal gene transfer is a significant driver of evolutionary dynamics across microbial populations. Although the benefits of the acquisition of new genetic material are often quite clear, experiments across systems have demonstrated that gene transfer events can cause significant phenotypic changes and entail fitness costs in a way that is dependent on the genomic and environmental context. Here, we test for the generality of one previously identified cost, sensitization of cells to the antibiotic nalidixic acid after acquisition of an ∼1-Mb megaplasmid, across strains and species. Overall, we find that the presence of this megaplasmid sensitizes many different strains to nalidixic acid but that this same horizontal gene transfer event increases resistance of KT2440 to nalidixic acid across assays as well as to ciprofloxacin under competitive conditions. These phenotypic results are not easily explained away as secondary consequences of overall fitness effects and appear to occur independently of another cost associated with this megaplasmid, sensitization to higher temperatures. Lastly, we draw parallels between these reported results and the phenomenon of sign epistasis for mutations and explore how context dependence of effects of plasmid acquisition could impact overall evolutionary dynamics and the evolution of antimicrobial resistance. Numerous studies have demonstrated that gene transfer events (e.g., plasmid acquisition) can entail a variety of costs that arise as by-products of the incorporation of foreign DNA into established physiological and genetic systems. These costs can be ameliorated through evolutionary time by the occurrence of compensatory mutations, which stabilize the presence of a horizontally transferred region within the genome but which also may skew future adaptive possibilities for these lineages. Here, we demonstrate another possible outcome, that phenotypic changes arising as a consequence of the same horizontal gene transfer (HGT) event are costly to some strains but may actually be beneficial in other genomic backgrounds under the right conditions. These results provide a new viewpoint for considering conditions that promote plasmid maintenance and highlight the influence of genomic and environmental contexts when considering amelioration of fitness costs after HGT events.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Gene Transfer Techniques; Genome, Bacterial; Nalidixic Acid; Plasmids; Pseudomonas putida
PubMed: 33597171
DOI: 10.1128/mSphere.00008-21 -
MBio Oct 2022The Gram-negative anaerobe Fusobacterium nucleatum is a major producer of hydrogen sulfide (HS), a volatile sulfur compound that causes halitosis. Here, we dissected the...
The Gram-negative anaerobe Fusobacterium nucleatum is a major producer of hydrogen sulfide (HS), a volatile sulfur compound that causes halitosis. Here, we dissected the genetic determinants of HS production and its role in bacterial fitness and virulence in this important member of the oral microbiome. F. nucleatum possesses four enzymes, CysK1, CysK2, Hly, and MegL, that presumably metabolize l-cysteine to HS, and CysK1 was previously shown to account for most HS production , based on correlations of enzymatic activities with gene expression at mid-log phase. Our molecular studies showed that and were highly expressed at the late exponential growth phase, concomitant with high-level HS production, while the expression levels of the other genes remained substantially lower during all growth phases. Although the genetic deletion of without supplementation with a CysK1-catalyzed product, lanthionine, caused cell death, the conditional Δ mutant and a mutant lacking were highly proficient in HS production. In contrast, a mutant devoid of showed drastically reduced HS production, and a mutant showed only minor deficiencies. Intriguingly, the exposure of these mutants to various antibiotics revealed that only the mutant displayed altered susceptibility compared to the parental strain: partial sensitivity to nalidixic acid and resistance to kanamycin. Most significantly, the mutant was attenuated in virulence in a mouse model of preterm birth, with considerable defects in the spread to amniotic fluid and the colonization of the placenta and fetus. Evidently, the l-methionine γ-lyase MegL is a major HS-producing enzyme in fusobacterial cells that significantly contributes to fusobacterial virulence and antibiotic susceptibility. Fusobacterium nucleatum is a key commensal anaerobe of the human oral cavity that plays a significant role in oral biofilm development and contributes to additional pathologies at extraoral sites, such as promoting preterm birth and colorectal cancer. Although F. nucleatum is known as a major producer of hydrogen sulfide (HS), its genetic determinants and physiological functions are not well understood. By a combination of bacterial genetics, biochemical methods, and models of infection, here, we demonstrate that the l-methionine γ-lyase MegL not only is a major HS-producing enzyme of F. nucleatum but also significantly contributes to the antibiotic susceptibility and virulence of this organism.
Topics: Infant, Newborn; Pregnancy; Mice; Animals; Female; Humans; Fusobacterium nucleatum; Hydrogen Sulfide; Virulence; Cysteine; Anti-Bacterial Agents; Nalidixic Acid; Premature Birth; Sulfur Compounds; Kanamycin
PubMed: 36073813
DOI: 10.1128/mbio.01936-22 -
PloS One 2019Shigellosis is the second leading cause of diarrheal death globally. The global burden has been complicated by the emergence of Shigella strains resistant to first line...
BACKGROUND
Shigellosis is the second leading cause of diarrheal death globally. The global burden has been complicated by the emergence of Shigella strains resistant to first line antibiotic treatments such as ciprofloxacin. This study aims to describe the epidemiologic distribution of the most common Shigella species, and their antimicrobial susceptibility patterns to ciprofloxacin and nalidixic acid (NA) in Latin America.
METHODS
Laboratory data from 19 countries were obtained through the Latin American Network for Antimicrobial Resistance Surveillance (ReLAVRA) from 2000-2015. The Clinical Laboratory Standards Institute reduced susceptibility breakpoints for Enterobacteriaceae was used to interpret the disc diffusion tests for Shigella susceptibility to ciprofloxacin and NA. Negative binominal regression was used to analyze longitudinal trends of Shigella isolates antimicrobial susceptibility.
RESULTS
79,548 Shigella isolates were tested and reported between 2000-2015. The most common isolated species were S. flexneri (49%), and S. sonnei (28%). There was a steady increase in the proportion of S. sonnei isolates within the region(p<0.001). The average annual percentage increase (AAPI) in nonsusceptibility was 18.4% (p<0.001) for ciprofloxacin (baseline = 0.3); and 13.2%(p<0.001) for NA (baseline = 3). AAPI nonsusceptibility to ciprofloxacin was 13.3% for S. flexneri (p<0.04); and 39.9% for S. sonnei (p<0.001). Honduras, Dominican Republic, Venezuela, and Chile reported the highest increase in nonsusceptibility to ciprofloxacin among all Shigella isolates.
CONCLUSION
There is an increasing trend in Shigella nonsusceptibility to ciprofloxacin and NA, including among the most common shigella species, in Latin America. This rise of nonsusceptibility among Shigella species to commonly used treatments such as ciprofloxacin is alarming and threatens the control and management of this currently treatable infection. Improved data quality, collection and reporting is needed in Latin America to respond effectively to the rising trends observed. This includes the need for quality isolate level epidemiological data; molecular data, and data on antibiotic consumption and use.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Bacterial; Humans; Latin America; Microbial Sensitivity Tests; Nalidixic Acid; Shigella
PubMed: 31374081
DOI: 10.1371/journal.pone.0220445 -
Antimicrobial Agents and Chemotherapy Jan 1983Norfloxacin, a new quinoline derivative, was studied in vitro, and determinations of agar dilution minimal inhibitory concentrations (MICs) and broth dilution MICs and...
Norfloxacin, a new quinoline derivative, was studied in vitro, and determinations of agar dilution minimal inhibitory concentrations (MICs) and broth dilution MICs and MBCs were made. Nalidixic acid and cinoxacin were used as comparative agents. Norfloxacin was found to be extremely active against all strains tested of Escherichia coli, Klebsiella spp., Proteus mirabilis, indole-positive Proteus spp. Serratia spp., Citrobacter spp., and Enterobacter spp., with MICs normally below 1 microgram/ml. It also was found to be highly active against Pseudomonas aeruginosa, Staphylococcus saprophyticus, and enterococci, which are all resistant to nalidixic acid and cinoxacin. The MICs for norfloxacin obtained by broth dilution were slightly higher than those obtained by agar dilution, whereas the reverse was true for nalidixic acid and cinoxacin. The MBCs of norfloxacin were only slightly higher than the MICs, even at high inocula. The in vitro activity of norfloxacin was not dependent on the inoculum size, whereas both the MICs and the MBCs of nalidixic acid increased markedly for many of the strains tested when the inoculum was increased in broth dilution from 10(3) to 10(6) colony-forming units per ml. Norfloxacin seems to be a promising antibacterial agent for the treatment of urinary tract infections, especially those caused by Pseudomonas spp. and other species today requiring the use of injectable antibiotics.
Topics: Anti-Bacterial Agents; Bacteria; Humans; Microbial Sensitivity Tests; Nalidixic Acid; Norfloxacin
PubMed: 6219617
DOI: 10.1128/AAC.23.1.15 -
Asian Pacific Journal of Tropical... Apr 2012To determine the effect of nalidixic acid on the morphology and protein expression of Pseudomonas aeruginosa (P. aeruginosa).
OBJECTIVE
To determine the effect of nalidixic acid on the morphology and protein expression of Pseudomonas aeruginosa (P. aeruginosa).
METHODS
Nalidixic acid solution of 1 600 μg/mL was prepared. The minimum inhibitory concentration (MIC) for P. aeruginosa was determined with tube dilution test. The effect of nalidixic acid on the morphology of P. aeruginosa was studied using light microscope and scanning electron microscope. Changes in protein profile were studied using SDS-PAGE.
RESULTS
The MIC of nalidixic acid was 700 μg/mL against P. aeruginosa. The exposure of P. aeruginosa to different concentrations of nalidixic acid resulted in deformation of most of the growing cells. At the concentration of 600 μg/mL most of the cells turned into elongated and adhere to each other while some of the cells were bulged. The intensity of protein bands were changed when they exposed to nalidixic acid.
CONCLUSIONS
The present findings suggest that the morphology and protein expression of P. aeruginosa is greatly affected by nalidixic acid.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Nalidixic Acid; Pseudomonas aeruginosa; Spectrophotometry
PubMed: 22449516
DOI: 10.1016/S1995-7645(12)60037-6 -
Antimicrobial Agents and Chemotherapy Jul 1980The chemotherapeutic properties of miloxacin (5,8-dihydro-5-methoxy-8-oxo-2H-1,3-dioxolo-[4,5-g]quinoline-7-carboxylic acid) have been compared with those of oxolinic... (Comparative Study)
Comparative Study
The chemotherapeutic properties of miloxacin (5,8-dihydro-5-methoxy-8-oxo-2H-1,3-dioxolo-[4,5-g]quinoline-7-carboxylic acid) have been compared with those of oxolinic acid and nalidixic acid. The in vitro activities of miloxacin (minimum inhibitory concentrations) against a variety of gram-negative bacteria, especially Enterobacteriaceae and Haemophilus, were comparable to those of oxolinic acid and 8 to 16 times greater than those of nalidixic acid. Miloxacin was more active than oxolinic acid against some anaerobes and less active against staphylococci. Miloxacin exhibited significant activities when administered orally to mice infected with Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, or Serratia marcescens. Its efficacy was comparable to that of oxolinic acid and two to four times greater than that of nalidixic acid. Miloxacin was less active against a Pseudomonas aeruginosa infection and inactive at the maximum test doses against a Streptococcus pyogenes infection.
Topics: 4-Quinolones; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Enterobacteriaceae; Mice; Microbial Sensitivity Tests; Nalidixic Acid; Oxolinic Acid
PubMed: 7416749
DOI: 10.1128/AAC.18.1.37