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1.
BMC Vet Res ; 20(1): 241, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831324

RESUMO

BACKGROUND: Actinobacillus pleuropneumoniae is a serious pathogen in pigs. The abundant application of antibiotics has resulted in the gradual emergence of drugresistant bacteria, which has seriously affected treatment of disease. To aid measures to prevent the emergence and spread of drug-resistant bacteria, herein, the kill rate and mutant selection window (MSW) of danofloxacin (DAN) against A. pleuropneumoniae were evaluated. METHODS: For the kill rate study, the minimum inhibitory concentration (MIC) was tested using the micro dilution broth method and time-killing curves of DAN against A. pleuropneumoniae grown in tryptic soy broth (TSB) at a series drug concentrations (from 0 to 64 MIC) were constructed. The relationships between the kill rate and drug concentrations were analyzed using a Sigmoid Emax model during different time periods. For the MSW study, the MIC99 (the lowest concentration that inhibited the growth of the bacteria by ≥ 99%) and mutant prevention concentration (MPC) of DAN against A. pleuropneumoniae were measured using the agar plate method. Then, a peristaltic pump infection model was established to simulate the dynamic changes of DAN concentrations in pig lungs. The changes in number and sensitivity of A. pleuropneumoniae were measured. The relationships between pharmacokinetic/pharmacodynamic parameters and the antibacterial effect were analyzed using the Sigmoid Emax model. RESULTS: In kill rate study, the MIC of DAN against A. pleuropneumoniae was 0.016 µg/mL. According to the kill rate, DAN exhibited concentration-dependent antibacterial activity against A. pleuropneumoniae. A bactericidal effect was observed when the DAN concentration reached 4-8 MIC. The kill rate increased constantly with the increase in DAN concentration, with a maximum value of 3.23 Log10 colony forming units (CFU)/mL/h during the 0-1 h period. When the drug concentration was in the middle part of the MSW, drugresistant bacteria might be induced. Therefore, the dosage should be avoided to produce a mean value of AUC24h/MIC99 (between 31.29 and 62.59 h. The values of AUC24h/MIC99 to achieve bacteriostatic, bactericidal, and eradication effects were 9.46, 25.14, and > 62.59 h, respectively. CONCLUSION: These kill rate and MSW results will provide valuable guidance for the use of DAN to treat A. pleuropneumoniae infections.


Assuntos
Infecções por Actinobacillus , Actinobacillus pleuropneumoniae , Antibacterianos , Fluoroquinolonas , Testes de Sensibilidade Microbiana , Actinobacillus pleuropneumoniae/efeitos dos fármacos , Actinobacillus pleuropneumoniae/genética , Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Animais , Infecções por Actinobacillus/veterinária , Infecções por Actinobacillus/tratamento farmacológico , Suínos , Farmacorresistência Bacteriana , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/microbiologia , Mutação
2.
PLoS One ; 19(5): e0301210, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38709710

RESUMO

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB), characterized by isoniazid and rifampicin resistance, is caused by chromosomal mutations that restrict treatment options and complicate tuberculosis management. This study sought to investigate the prevalence of pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) tuberculosis, as well as mutation pattern, in Nepalese patients with MDR/rifampicin-resistant (RR)-TB strains. METHODS: A cross-sectional study was conducted on MDR/RR-TB patients at the German Nepal Tuberculosis Project from June 2017 to June 2018. The MTBDRsl line probe assay identified pre-XDR-TB and XDR-TB. Pre-XDR-TB included MDR/RR-TB with resistance to any fluoroquinolone (FLQ), while XDR-TB included MDR/RR-TB with resistance to any FLQ and at least one additional group A drug. Mutation status was determined by comparing bands on reaction zones [gyrA and gyrB for FLQ resistance, rrs for SILD resistance, and eis for low-level kanamycin resistance, according to the GenoType MTBDRsl VER 2.0, Hain Lifescience GmbH, Nehren, Germany definition of pre-XDR and XDR] to the evaluation sheet. SPSS version 17.0 was used for data analysis. RESULTS: Out of a total of 171 patients with MDR/RR-TB, 160 had (93.57%) had MTBC, of whom 57 (35.63%) had pre-XDR-TB and 10 (6.25%) had XDR-TB. Among the pre-XDR-TB strains, 56 (98.25%) were FLQ resistant, while 1 (1.75%) was SLID resistant. The most frequent mutations were found at codons MUT3C (57.14%, 32/56) and MUT1 (23.21%, 13/56) of the gyrA gene. One patient had SLID resistant genotype at the MUT1 codon of the rrs gene (100%, 1/1). XDR-TB mutation bands were mostly detected on MUT1 (30%, 3/10) of the gyrA and rrs, MUT3C (30%, 3/10) of the gyrA, and MUT1 (30%, 3/10) of the rrs. CONCLUSIONS: Pre-XDR-TB had a significantly higher likelihood than XDR-TB, with different specific mutation bands present in gyrA and rrs genes.


Assuntos
Antituberculosos , Tuberculose Extensivamente Resistente a Medicamentos , Mutação , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Nepal/epidemiologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Masculino , Feminino , Adulto , Estudos Transversais , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Pessoa de Meia-Idade , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Testes de Sensibilidade Microbiana , Rifampina/uso terapêutico , Rifampina/farmacologia , Isoniazida/uso terapêutico , Isoniazida/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Adulto Jovem , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Adolescente , Idoso
4.
West Afr J Med ; 41(3): 301-310, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38788127

RESUMO

INTRODUCTION: According to the World Health Organization, antimicrobial resistance (AMR) is a silent global pandemic that plagues everyone. It makes therapy of infectious diseases more difficult and eventually increases morbidity and mortality. AIM: The purpose of this work is to examine existing data on plasmid-mediated quinolone resistance (PMQR), to assess the prevalence of PMQR genes in Enterobacterales, and to determine any knowledge gaps from sub-Saharan Africa. METHODOLOGY: The Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) standard was followed when conducting this systematic review. The main internet databases examined for pertinent publications were PubMed, Google Scholar, and Ajol. A set of qualifying criteria were used to evaluate the qualified articles. Using the eligibility criteria, 56 full-text articles were chosen for screening. RESULT: Thirty-two (32) articles with the majority originating from West and North Africa and only one article reporting a study carried out in Central Africa were selected for this review. Escherichia coli and Ciprofloxacin were the most reported Enterobacterales and Quinolone respectively. The PMQR genes include qnr (qnrA,qnrB, qnrC, qnrD, and qnrS), aac (6') Ib, aac (6') Ib-cr, oqxAB and qepA gene. The most prevalent PMQR gene is the aac (6') Ib-cr gene (32%) followed by qnrS (26%). CONCLUSION: This study highlighted the requirement for an efficient antimicrobial resistance surveillance system in the continent and revealed a significant incidence of PMQR genes.


INTRODUCTION: Selon l'Organisation mondiale de la santé, la résistance aux antimicrobiens (RAM) est une pandémie mondiale silencieuse qui touche tout le monde. Elle rend le traitement des maladies infectieuses plus difficile et finit par augmenter la morbidité et la mortalité. OBJECTIF: L'objectif de ce travail est d'examiner les données existantes sur la résistance plasmidique aux quinolones (PMQR), d'évaluer la prévalence des gènes PMQR chez les Enterobacterales et de déterminer d'éventuelles lacunes de connaissances en Afrique subsaharienne. MÉTHODOLOGIE: La norme Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) a été suivie lors de la réalisation de cette revue systématique. Les principales bases de données Internet examinées pour des publications pertinentes étaient PubMed, Google Scholar et Ajol. Un ensemble de critères d'admissibilité a été utilisé pour évaluer les articles qualifiés. En utilisant les critères d'éligibilité, 56 articles en texte intégral ont été choisis pour le dépistage. RÉSULTAT: Trente-deux (32) articles, dont la majorité provient d'Afrique de l'Ouest et du Nord, et un seul article rapportant une étude menée en Afrique centrale, ont été sélectionnés pour cette revue. Escherichia coli et la ciprofloxacine étaient les Enterobacterales et les quinolones les plus signalées respectivement. Les gènes PMQR comprennent les gènes qnr (qnrA, qnrB, qnrC, qnrD et qnrS), aac (6 ') Ib, aac (6 ') Ib-cr, oqxAB et qepA. Le gène PMQR le plus prévalent est le gène aac (6 ') Ib-cr (32 %), suivi de qnrS (26 %). CONCLUSION: Cette étude a souligné la nécessité d'un système efficace de surveillance de la résistance aux antimicrobiens sur le continen`t et a révélé une incidence significative des gènes PMQR. MOTS-CLÉS: Enterobacterales, Escherichia coli, Quinolone, Ciprofloxacine, PMQR, "aac(6')-Ib", "aac(6')-Ib-cr", "qnr", "qepA", "oqxAB", "résistance aux antibiotiques".


Assuntos
Antibacterianos , Farmacorresistência Bacteriana , Infecções por Enterobacteriaceae , Enterobacteriaceae , Fluoroquinolonas , Plasmídeos , Humanos , Fluoroquinolonas/farmacologia , Antibacterianos/farmacologia , Plasmídeos/genética , Farmacorresistência Bacteriana/genética , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/epidemiologia , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , África/epidemiologia
5.
Sci Total Environ ; 935: 173346, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-38777063

RESUMO

Antibiotics, one of the significant emerging contaminants, are intensifying their continual spread out into the environment and affecting human health and the ecosystem in the developing country Bangladesh. This study characterizes widely used fluoroquinolone (FQ) antibiotics, formulates the method to spectrally distinguish them from ubiquitous, and important reactive, adsorbent, and altering catalytic macromolecule humic substances (HS), and further quantifies them using fluorescence spectroscopy. The presence of identical fluorophore at Excitation/Emission = 225-230/285-295 nm wavelength, possession of fluorescence spectra at short emission wavelength (<350 nm) during 275 nm excitation, different emission maxima, and various fluorescing components in antibiotics identified through three-dimensional excitation-emission matrix (EEM) and parallel factor analysis (PARAFAC) models distinguished them from the humic substance as well as from each other. Stern-Volmer equation and its modified version were applied to identify quenching and binding capability, and fluorescence intensity quenching rate of antibiotics and humic in their mixture. Unlike poor and inconsistent quenching mechanisms of humic, FQ antibiotics reduced HS intensity throughout the entire photo-irradiation experiment affirming the functioning of the stable quenching methods. Static quenching of fluorophores was identified from the redshift of excited wavelength on the electronic ground state. Temperature differences during daylight and dark conditions played contrasting roles during the fluorescence quenching of FQ. Unique spectral response at emission wavelength < 350 nm during 275 nm excitation in FQ was considered as its least intensity in the antibiotic-humic mixture and was also used to formulate distinct spectral pattern of each FQ antibiotic. The study also identified the traces of FQ antibiotics with various intensities at different lakes in Bangladesh.


Assuntos
Antibacterianos , Fluoroquinolonas , Substâncias Húmicas , Espectrometria de Fluorescência , Antibacterianos/análise , Substâncias Húmicas/análise , Fluoroquinolonas/análise , Poluentes Químicos da Água/análise , Bangladesh , Monitoramento Ambiental/métodos
6.
Sci Rep ; 14(1): 12066, 2024 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802465

RESUMO

Heterogeneity of Helicobacter pylori communities contributes to its pathogenicity and diverse clinical outcomes. We conducted drug-susceptibility tests using four antibiotics, clarithromycin (CLR), amoxicillin (AMX), metronidazole and sitafloxacin, to examine H. pylori population diversity. We also analyzed genes associated with resistance to CLR and AMX. We examined multiple isolates from 42 Japanese patients, including 28 patients in whom primary eradication with CLR and AMX had failed, and 14 treatment-naïve patients. We identified some patients with coexistence of drug resistant- and sensitive-isolates (drug-heteroR/S-patients). More than 60% of patients were drug-heteroR/S to all four drugs, indicating extensive heterogeneity. For the four drugs except AMX, the rates of drug-heteroR/S-patients were higher in treatment-naïve patients than in primary eradication-failure patients. In primary eradication-failure patients, isolates multi-resistant to all four drugs existed among other isolates. In primary eradication-failure drug-heteroR/S-patients, CLR- and AMX-resistant isolates were preferentially distributed to the corpus and antrum with different minimum inhibitory concentrations, respectively. We found two mutations in PBP1A, G591K and A480V, and analyzed these in recombinants to directly demonstrate their association with AMX resistance. Assessment of multiple isolates from different stomach regions will improve accurate assessment of H. pylori colonization status in the stomach.


Assuntos
Amoxicilina , Antibacterianos , Farmacorresistência Bacteriana , Infecções por Helicobacter , Helicobacter pylori , Testes de Sensibilidade Microbiana , Mutação , Humanos , Helicobacter pylori/genética , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/isolamento & purificação , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genética , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , Masculino , Feminino , Metronidazol/farmacologia , Estômago/microbiologia , Claritromicina/farmacologia , Pessoa de Meia-Idade , Idoso , Adulto , Proteínas de Bactérias/genética , Proteínas de Ligação às Penicilinas/genética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico
7.
BMC Microbiol ; 24(1): 175, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773370

RESUMO

BACKGROUND: Data about the prevalence of plasmid-mediated quinolone resistance (PMQR) and extended-spectrum beta-lactamase (ESBL) production in P. aeruginosa compared to the Enterobacteriaceae family is limited. The availability of limited therapeutic options raises alarming concerns about the treatment of multidrug-resistant P. aeruginosa. This study aimed to assess the presence of PMQR and ESBL genes among P. aeruginosa strains. METHODS: Fifty-six P. aeruginosa strains were isolated from 330 patients with different clinical infections. Phenotypically fluoroquinolone-resistant isolates were tested by PCR for the presence of six PMQR genes. Then, blaTEM, blaSHV, and blaCTX-M type ESBL genes were screened to study the co-existence of different resistance determinants. RESULTS: Overall, 22/56 (39.3%) of the studied P. aeruginosa isolates were phenotypically resistant to fluoroquinolones. PMQR-producing P. aeruginosa isolates were identified in 20 isolates (90.9%). The acc(6')-Ib-cr was the most prevalent PMQR gene (77.3%). The qnr genes occurred in 72.7%, with the predominance of the qnrA gene at 54.5%, followed by the qnrS gene at 27.3%, then qnrB and qnrC at 22.7%. The qepA was not detected in any isolate. The acc(6')-Ib-cr was associated with qnr genes in 65% of positive PMQR isolates. Significant differences between the fluoroquinolone-resistant and fluoroquinolone-susceptible isolates in terms of the antibiotic resistance rates of amikacin, imipenem, and cefepime (P value < 0.0001) were found. The ESBL genes were detected in 52% of cephalosporin-resistant P. aeruginosa isolates. The most frequent ESBL gene was blaCTX-M (76.9%), followed by blaTEM (46.2%). No isolates carried the blaSHV gene. The acc(6')-Ib-cr gene showed the highest association with ESBL genes, followed by the qnrA gene. The correlation matrix of the detected PMQR and ESBL genes indicated overall positive correlations. The strongest and most highly significant correlation was between qnrA and acc(6')-Ib-cr (r = 0.602) and between qnrA and blaCTX-M (r = 0.519). CONCLUSION: A high prevalence of PMQR genes among the phenotypic fluoroquinolone-resistant P. aeruginosa isolates was detected, with the co-carriage of different PMQR genes. The most frequent PMQR was the acc(6')-Ib-cr gene. Co-existence between PMQR and ESBL genes was found, with 75% of PMQR-positive isolates carrying at least one ESBL gene. A high and significant correlation between the ESBL and PMQR genes was detected.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Plasmídeos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Quinolonas , beta-Lactamases , Humanos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/enzimologia , beta-Lactamases/genética , Egito , Plasmídeos/genética , Antibacterianos/farmacologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/epidemiologia , Quinolonas/farmacologia , Farmacorresistência Bacteriana/genética , Farmacorresistência Bacteriana Múltipla/genética , Fluoroquinolonas/farmacologia , Adulto , Feminino , Masculino
8.
J Pharmacol Toxicol Methods ; 127: 107510, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38705245

RESUMO

Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies. We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls. Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP. The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies.


Assuntos
Eletrocardiografia , Fluoroquinolonas , Moxifloxacina , Telemetria , Animais , Feminino , Eletrocardiografia/métodos , Eletrocardiografia/efeitos dos fármacos , Masculino , Telemetria/métodos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Grupos Controle , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Estado de Consciência/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos
9.
Medicine (Baltimore) ; 103(18): e38012, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38701320

RESUMO

Success in eradication of H. pylori is decreasing due to increasing resistant strains. In particular, side-effects due to 4-agent treatment multiple drug use are observed and treatment compliance decreases. The aim of this study was to evaluate the efficacy, reliability, and side-effect profile of the combination of amoxicillin and rabeprazole with gemifloxacin, which is a new generation quinolone, in the treatment of H. pylori infection. This study was conducted on 71 naive patients who received H. pylori eradication. All the patients were administered treatment of Amoxicillin (1000 mg twice a day) + Gemifloxacin (320 mg once a day) + rabeprazole (20 mg twice a day) for 7 days. Drug compliance and treatment tolerance were evaluated after finishing the treatment. At 1 month after the end of the treatment, H. pylori eradication was evaluated in all the patients by examining H. pylori antigen in the feces. In the evaluation after treatment, H. pylori eradication was obtained in 63 (88.7%) patients and eradication was not obtained in 8 (11.3%) patients. The treatment was not completed by 2 patients because of side-effects and noncompliance, so after exclusion of these 2 patients, successful H. pylori eradication was obtained in 63 (91.3%) of 69 patients who completed the treatment. Side-effects were seen in a total of 9 (12.7%) patients. Diarrhea, bloating, abdominal pain, and nausea-vomiting were seen in some patients, but no reflux, constipation, skin rash, listlessness-fatigue, headache, dizziness, palpitations, dry mouth, or weight loss was seen in any patient. In regions with high resistance to clarithromycin and metronidazole in particular, the combination of gemifloxacin with amoxicillin and rabeprazole can be considered for use in first-stage treatment as both the efficacy and tolerability are high.


Assuntos
Amoxicilina , Antibacterianos , Quimioterapia Combinada , Fluoroquinolonas , Gemifloxacina , Infecções por Helicobacter , Helicobacter pylori , Rabeprazol , Humanos , Rabeprazol/administração & dosagem , Rabeprazol/uso terapêutico , Amoxicilina/administração & dosagem , Amoxicilina/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Masculino , Feminino , Projetos Piloto , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Pessoa de Meia-Idade , Adulto , Fluoroquinolonas/uso terapêutico , Fluoroquinolonas/administração & dosagem , Resultado do Tratamento , Idoso
10.
ACS Infect Dis ; 10(4): 1351-1360, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38606464

RESUMO

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 Neisseria gonorrhoeae, 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 N. gonorrhoeae.


Assuntos
Ciprofloxacina , Gonorreia , Humanos , Ciprofloxacina/farmacologia , Fluoroquinolonas/farmacologia , DNA Topoisomerase IV/genética , DNA Topoisomerase IV/metabolismo , Neisseria gonorrhoeae , Gonorreia/tratamento farmacológico , Gonorreia/microbiologia , DNA Girase/genética , DNA Girase/metabolismo , Testes de Sensibilidade Microbiana
11.
Int J Mol Sci ; 25(7)2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38612501

RESUMO

Increased evidence has documented a direct association between Ciprofloxacin (CFX) intake and significant disruption to the normal functions of connective tissues, leading to severe health conditions (such as tendonitis, tendon rupture and retinal detachment). Additionally, CFX is recognized as a potential emerging pollutant, as it seems to impact both animal and human food chains, resulting in severe health implications. Consequently, there is a compelling need for the precise, swift and selective detection of this fluoroquinolone-class antibiotic. Herein, we present a novel graphene-based electrochemical sensor designed for Ciprofloxacin (CFX) detection and discuss its practical utility. The graphene material was synthesized using a relatively straightforward and cost-effective approach involving the electrochemical exfoliation of graphite, through a pulsing current, in 0.05 M sodium sulphate (Na2SO4), 0.05 M boric acid (H3BO3) and 0.05 M sodium chloride (NaCl) solution. The resulting material underwent systematic characterization using scanning electron microscopy/energy dispersive X-ray analysis, X-ray powder diffraction and Raman spectroscopy. Subsequently, it was employed in the fabrication of modified glassy carbon surfaces (EGr/GC). Linear Sweep Voltammetry studies revealed that CFX experiences an irreversible oxidation process on the sensor surface at approximately 1.05 V. Under optimal conditions, the limit of quantification was found to be 0.33 × 10-8 M, with a corresponding limit of detection of 0.1 × 10-8 M. Additionally, the developed sensor's practical suitability was assessed using commercially available pharmaceutical products.


Assuntos
Ciprofloxacina , Grafite , Animais , Humanos , Fluoroquinolonas , Carbono , Eletrodos
12.
J Infect Dev Ctries ; 18(3): 399-406, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38635612

RESUMO

INTRODUCTION: Although fluoroquinolones are used to treat methicillin-resistant Staphylococcus aureus (MRSA)-induced infections, acquisition of antibiotic resistance by bacteria has impaired their clinical relevance. We aimed to evaluate the frequency of norA, norB, and norC efflux pump genes-mediating fluoroquinolones resistance and measure their expression levels in MRSA isolates. METHODOLOGY: 126 S. aureus isolates were collected from different clinical samples of adult hospitalized patients and identified by conventional microbiological methods. MRSA was diagnosed by cefoxitin disc diffusion method and minimum inhibitory concentration (MIC) of ciprofloxacin by broth microdilution method. The expression levels of efflux pump genes were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: 80 (63.5%) MRSA isolates were identified and showed high level of resistance to erythromycin (80%), gentamicin (75%), clindamycin (65%) and ciprofloxacin (60 %). norA, norB and norC were detected in 75%, 35% and 55% of the MRSA isolates respectively. norC was the most commonly overexpressed gene measured by qRT-PCR, occurring in 40% of MRSA isolates, followed by norA (35%) and norB (30%). The expression of these genes was significantly higher in ciprofloxacin-resistant than quantitative real-time PCR ciprofloxacin-sensitive MRSA isolates. CONCLUSIONS: This study showed high prevalence and overexpression of efflux pump genes among MRSA isolates which indicates the significant role of these genes in the development of multidrug resistance against antibiotics including fluoroquinolones.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Fluoroquinolonas/farmacologia , Staphylococcus aureus , Infecções Estafilocócicas/microbiologia , Proteínas de Bactérias/genética , Ciprofloxacina/farmacologia , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana
13.
Pol Merkur Lekarski ; 52(2): 197-202, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38642355

RESUMO

OBJECTIVE: Aim: The goal is to discover QSAR of Lomefloxacin as antibacterial activity. PATIENTS AND METHODS: Materials and Methods: A number of lomefloxacins analogs activities were studied by program Windows Chem SW. The analogues were obtained and energy minimization was carried out through Molecular Modeling Program, the calculations were performed using General Atomic and Molecular Electronic Structure System (GAMESS) software. RESULTS: Results: There were six descriptions (N-quinoline more (-) ev charge, Kinetic Energy, Potential Energy, Log p, Log S, F6 charge) results have highly compatible of physicochemical properties with lomefloxacin analogs activities. It can be used to estimate the activities depending on QSAR equation of lomefloxacin analogs. CONCLUSION: Conclusions: The parameters used for calculation were depending on the quantum chemical was employed in deriving from computational study of properties and can used to predict the activities of certain analogs of Lomefloxacins as antibacterial compounds.


Assuntos
Fluoroquinolonas , Relação Quantitativa Estrutura-Atividade , Humanos , Fluoroquinolonas/farmacologia , Modelos Moleculares , Antibacterianos/farmacologia
14.
ACS Infect Dis ; 10(4): 1097-1115, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38564341

RESUMO

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, Mycobacterium tuberculosis 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.


Assuntos
DNA Topoisomerase IV , Mycobacterium tuberculosis , DNA Topoisomerase IV/genética , Fluoroquinolonas/farmacologia , DNA Girase/genética , DNA Girase/metabolismo , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/farmacologia , Antibacterianos/metabolismo , DNA/metabolismo , Mycobacterium tuberculosis/genética
15.
J Hazard Mater ; 470: 133740, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38569335

RESUMO

The fate of fluoroquinolone antibiotics norfloxacin and ofloxacin were investigated in mesocosmic wetlands, along with their effects on nutrients removal, antibiotic resistance genes (ARGs) and epiphytic microbial communities on Hydrilla verticillate using bionic plants as control groups. Approximately 99% of norfloxacin and ofloxacin were removed from overlaying water, and H. verticillate inhibited fluoroquinolones accumulation in surface sediments compared to bionic plants. Partial least squares path modeling showed that antibiotics significantly inhibited the nutrient removal capacity (0.55) but had no direct effect on plant physiology. Ofloxacin impaired wetland performance more strongly than norfloxacin and more impacted the primary microbial phyla, whereas substrates played the most decisive role on microbial diversities. High antibiotics concentration shifted the most dominant phyla from Proteobacteria to Bacteroidetes and inhibited the Xenobiotics biodegradation function, contributing to the aggravation in wetland performance. Dechloromonas and Pseudomonas were regarded as the key microorganisms for antibiotics degradation. Co-occurrence network analysis excavated that microorganisms degrade antibiotics mainly through co-metabolism, and more complexity and facilitation/reciprocity between microbes attached to submerged plants compared to bionic plants. Furthermore, environmental factors influenced ARGs mainly by altering the community dynamics of differential bacteria. This study offers new insights into antibiotic removal and regulation of ARGs accumulation in wetlands with submerged macrophyte.


Assuntos
Antibacterianos , Biodegradação Ambiental , Microbiota , Norfloxacino , Poluentes Químicos da Água , Áreas Alagadas , Antibacterianos/farmacologia , Poluentes Químicos da Água/metabolismo , Norfloxacino/farmacologia , Microbiota/efeitos dos fármacos , Hydrocharitaceae/metabolismo , Hydrocharitaceae/genética , Resistência Microbiana a Medicamentos/genética , Ofloxacino , Bactérias/genética , Bactérias/metabolismo , Bactérias/efeitos dos fármacos , Genes Bacterianos , Fluoroquinolonas/metabolismo
17.
Eur Rev Med Pharmacol Sci ; 28(6): 2522-2537, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38567612

RESUMO

OBJECTIVE: Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter acetylcholine has been related to the etiology of Alzheimer's disease. Acetylcholinesterase is an enzyme that breaks down acetylcholine to an inactive form and causes the death of cholinergic neurons. Conventional treatments were used but had less effectiveness. Therefore, there is a crucial need to identify alternative compounds with potential anti-cholinesterase agents and minimal undesirable effects. MATERIALS AND METHODS: Fluoroquinolones and benzimidazole-benzothiazole derivatives offer antimicrobial, anti-inflammatory, anti-oxidant, anti-diabetic, and anti-Alzheimer activities. To enhance the chemical portfolio of cholinesterase inhibitors, a variety of fluoroquinolones and benzimidazole-benzothiazole compounds were evaluated against acetylcholinesterase (AChE) butyrylcholinesterase (BChE) enzymes. For this purpose, molecular docking and adsorption, distribution, metabolism, excretion, and toxicology ADMET models were used for in-silico studies for both AChE and BChE enzymes to investigate possible binding mechanisms and drug-likeness of the compounds. The inhibitory effect of docked heterocyclic compounds was also verified in vitro against AChE and BChE enzymes. Fluoroquinolones (Z, Z3, Z4, Z6, Z8, Z12, Z15, and Z9) and benzimidazole-benzothiazole compounds (TBIS-16, TBAF-1 to 9) passed through the AChE inhibition assay and their IC50 values were calculated. RESULTS: The compound 1-ethyl-6-fluoro-7-(4-(2-(4-nitrophenylamino)-2-oxoethyl)piperazin-1-yl) -4-oxo-1,4 di-hydroquinoline-3-carboxylic acid and 2-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(3-bromobenzyl)-4-hydroxy-2H-thiochromene-3-carbohydrazide 1,1-dioxide (Z-9 and TBAF-6) showed the lowest IC50 values against AChE/BChE (0.37±0.02/2.93±0.03 µM and 0.638±0.001/1.31±0.01 µM, respectively) than the standard drug, donepezil (3.9±0.01/4.9±0.05 µM). During the in-vivo investigation, behavioral trials were performed to analyze the neuroprotective impact of Z-9 and TBAF-6 compounds on AD mouse models. The groups treated with Z-9 and TBAF-6 compounds had better cognitive behavior than the standard drug. CONCLUSIONS: This study found that Z-9 (Fluoroquinolones) and TBAF-6 (benzimidazole-benzothiazole) compounds improve behavioral and biochemical parameters, thus treating neurodegenerative disorders effectively.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Camundongos , Animais , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Acetilcolinesterase/metabolismo , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Butirilcolinesterase/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Acetilcolina , Simulação de Acoplamento Molecular , Benzotiazóis/uso terapêutico , Benzimidazóis/uso terapêutico , Fluoroquinolonas/uso terapêutico , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 271: 116399, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38640868

RESUMO

The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 µg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.


Assuntos
Antibacterianos , Fluoroquinolonas , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Pirimidinas , Quinolonas , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Relação Estrutura-Atividade , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Fluoroquinolonas/farmacologia , Fluoroquinolonas/química , Fluoroquinolonas/síntese química , Quinolonas/farmacologia , Quinolonas/química , Quinolonas/síntese química , Estrutura Molecular , Farmacorresistência Bacteriana/efeitos dos fármacos , Relação Dose-Resposta a Droga , Animais , Humanos
19.
Front Public Health ; 12: 1356826, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38566794

RESUMO

Purpose: This study examined the patterns and frequency of genetic changes responsible for resistance to first-line (rifampicin and isoniazid), fluoroquinolones, and second-line injectable drugs in drug-resistant Mycobacterium tuberculosis (MTB) isolated from culture-positive pulmonary tuberculosis (PTB) symptomatic attendees of spiritual holy water sites (HWSs) in the Amhara region. Patients and methods: From June 2019 to March 2020, a cross-sectional study was carried out. A total of 122 culture-positive MTB isolates from PTB-suspected attendees of HWSs in the Amhara region were evaluated for their drug resistance profiles, and characterized gene mutations conferring resistance to rifampicin (RIF), isoniazid (INH), fluoroquinolones (FLQs), and second-line injectable drugs (SLIDs) using GenoType®MTBDRplus VER2.0 and GenoType®MTBDRsl VER2.0. Drug-resistant MTB isolates were Spoligotyped following the manufacturer's protocol. Results: Genetic changes (mutations) responsible for resistance to RIF, INH, and FLQs were identified in 15/122 (12.3%), 20/122 (16.4%), and 5/20 (25%) of MTB isolates, respectively. In RIF-resistant, rpoB/Ser531Lue (n = 12, 80%) was most frequent followed by His526Tyr (6.7%). Amongst INH-resistant isolates, katG/Ser315Thr1 (n = 19, 95%) was the most frequent. Of 15 MDR-TB, the majority (n = 12, 80%) isolates had mutations at both rpoB/Ser531Leu and katG/Ser315Thr1. All 20 INH and/or RIF-resistant isolates were tested with the MTBDRsl VER 2.0, yielding 5 FLQs-resistant isolates with gene mutations at rpoB/Ser531Lue, katG/Ser315Thr1, and gyrA/Asp94Ala genes. Of 20 Spoligotyped drug-resistant MTB isolates, the majority (n = 11, 55%) and 6 (30%) were SIT149/T3-ETH and SIT21/CAS1-Kili sublineages, respectively; and they were any INH-resistant (mono-hetero/multi-). Of 15 RIF-resistant (RR/MDR-TB) isolates, 7 were SIT149/T3-ETH, while 6 were SIT21/CAS1-Kili sublineages. FLQ resistance was detected in four SIT21/CAS1-Kili lineages. Conclusion: In the current study, the most common gene mutations responsible for resistance to INH, RIF, and FLQs were identified. SIT149/T3-ETH and SIT21/CAS1-Kili constitute the majority of drug-resistant TB (DR-TB) isolates. To further understand the complete spectrum of genetic changes/mutations and related genotypes, a sequencing technology is warranted.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose Pulmonar , Tuberculose , Humanos , Mycobacterium tuberculosis/genética , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Isoniazida/farmacologia , Rifampina/farmacologia , Etiópia , Estudos Transversais , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Mutação , Genótipo , Fluoroquinolonas
20.
Int J Mol Sci ; 25(8)2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38674148

RESUMO

It is now generally accepted that the success of antitumor therapy can be impaired by concurrent antibiotic therapy, the presence of certain bacteria, and elevated defensin levels around the tumor tissue. The aim of our current investigation was to identify the underlying changes in microbiome and defensin levels in the tumor tissue induced by different antibiotics, as well as the duration of this modification. The microbiome of the tumor tissues was significantly different from that of healthy volunteers. Comparing only the tumor samples, no significant difference was confirmed between the untreated group and the group treated with antibiotics more than 3 months earlier. However, antibiotic treatment within 3 months of analysis resulted in a significantly modified microbiome composition. Irrespective of whether Fosfomycin, Fluoroquinolone or Beta-lactam treatment was used, the abundance of Bacteroides decreased, and Staphylococcus abundance increased. Large amounts of the genus Acinetobacter were observed in the Fluoroquinolone-treated group. Regardless of the antibiotic treatment, hBD1 expression of the tumor cells consistently doubled. The increase in hBD2 and hBD3 expression was the highest in the Beta-lactam treated group. Apparently, antibiotic treatment within 3 months of sample analysis induced microbiome changes and defensin expression levels, depending on the identity of the applied antibiotic.


Assuntos
Antibacterianos , Microbiota , Neoplasias da Bexiga Urinária , beta-Defensinas , Humanos , beta-Defensinas/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/microbiologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Microbiota/efeitos dos fármacos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Fosfomicina/uso terapêutico , Fosfomicina/farmacologia , Fluoroquinolonas/uso terapêutico , Fluoroquinolonas/farmacologia , beta-Lactamas/uso terapêutico , beta-Lactamas/farmacologia
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