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1.
Eur J Med Res ; 28(1): 3, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36593500

RESUMO

BACKGROUND: Resistance to different antimicrobial classes by Salmonella species has generated a global public health concern. The spread of extended-spectrum ß-lactamases (ESBLs) blaCTX gene variants is also increasing. This study aimed to investigate the antibiotic resistance and the carriage of blaCTX-M-9 and blaCTX-M-15 as well as the quinolone resistance gene (qnrB19) among Salmonella species from hospitalised patients in Lagos, Nigeria. METHODS: In this cross-sectional study from April 2021 to August 2021, a total of 508 samples were collected from hospitalised patients. The samples were subjected to standard microbiological investigation. All the isolates were identified using API 20E kits and real-time polymerase chain reaction (RT-PCR). The in vitro antibiotic susceptibility testing (AST) was investigated using the disk diffusion method. Detection of antibiotic resistance and virulence gene makers was conducted using RT-PCR. RESULTS: In total, 24 Salmonella species were identified. All the isolates were non-typhoidal Salmonella isolates. None of the isolates screened was S. Typhi and S. Paratyphi. Most of the isolates were susceptible to imipenem, ciprofloxacin, ofloxacin and gentamycin, while a high level of resistance to all cephalosporins, penicillin, and some carbapenems was observed. In total, 79.2% (19/24) of the Salmonella isolates harboured the blaCTX-M variant including 54.2% (13/24) blaCTX-M-9 and 12.5% (3/24) blaCTX-M-15, while co-habitation of blaCTX-M-9 and blaCTX-M-15 was observed in 12.5% (3/24) of the isolates, respectively. None of the isolates harboured quinolone-resistant qnrB19 gene and virulence gene stn. However, invA gene was present in 66.7% (16/24) of all isolates. CONCLUSIONS: This study is considered the first report of blaCTX-M-9 and blaCTX-M-15 variants in Salmonella species in Nigeria. The continued existence of cefotaximase (CTX-M)-producing Salmonella within our environment calls for the prudent use of cephalosporins.


Assuntos
Salmonella , beta-Lactamases , Humanos , Antibacterianos/farmacologia , beta-Lactamases/genética , Cefalosporinas , Estudos Transversais , Nigéria/epidemiologia , Quinolonas , Salmonella/genética
2.
PLoS One ; 18(1): e0280150, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36630464

RESUMO

BACKGROUND: Antibiotic resistance has become an enduring threat to human health. This has prompted extensive research to identify the determinants responsible in a bid to fight the spread of resistance and also develop new antibiotics. However, routine procedures focus on identifying genetic determinants of resistance only on phenotypically resistant isolates. We aimed to characterise plasmid mediated resistance determinants in key Enterobacteriaceae isolates with differential phenotypic susceptibility profiles and evaluated the contribution of resistance genes on phenotypic expression of susceptibility. METHODS: The study was carried out on 200 Enterobacteriaceae isolates belonging to the genera E. coli, Salmonella, and Klebsiella; 100 resistant and 100 susceptible to quinolones, aminoglycosides, and ESBL-producing as determined by disk diffusion. Reduced susceptibility in susceptible isolates was determined as an increased MIC by broth microdilution. Plasmid-borne resistance genes were sought in all isolates by endpoint PCR. We performed correlations tests to determine the relationship between the occurrence of resistance genes and increased MIC in susceptible isolates. We then used the notion of penetrance to show adequacy between resistance gene carriage and phenotypic resistance as well as diagnostic odds ratio to evaluate how predictable phenotypic susceptibility profile could determine the presence of resistant genes in the isolates. RESULTS: Reduced susceptibility was detected in 30% (9/30) ESBL negative, 50% (20/40) quinolone-susceptible and 53.33% (16/30) aminoglycoside-susceptible isolates. Plasmid-borne resistance genes were detected in 50% (15/30) of ESBL negative, 65% (26/40) quinolone susceptible and 66.67% (20/30) aminoglycoside susceptible isolates. Reduced susceptibility increased the risk of susceptible isolates carrying resistance genes (ORs 4.125, 8.36, and 8.89 respectively for ESBL, quinolone, and aminoglycoside resistance genes). Resistance gene carriage correlated significantly to reduced susceptibility for quinolone and aminoglycoside resistance genes (0.002 and 0.015 at CI95). Gene carriage correlated with phenotypic resistance at an estimated 64.28% for ESBL, 56.90% for quinolone, and 58.33% for aminoglycoside resistance genes. CONCLUSIONS: A high carriage of plasmid-mediated genes for ESBL, quinolone, and aminoglycoside resistance was found among the Enterobacteriaceae tested. However, gene carriage was not always correlated with phenotypic expression. This allows us to suggest that assessing genetic determinants of resistance should not be based on AST profile only. Further studies, including assessing the role of chromosomal determinants will shed light on other factors that undermine antimicrobial susceptibility locally.


Assuntos
Escherichia coli , Quinolonas , Animais , Humanos , Escherichia coli/metabolismo , Antibacterianos/farmacologia , Klebsiella/genética , Klebsiella/metabolismo , Galinhas/genética , Camarões , beta-Lactamases/genética , Farmacorresistência Bacteriana/genética , Plasmídeos/genética , Aminoglicosídeos/farmacologia , Quinolonas/farmacologia , Salmonella/genética , Salmonella/metabolismo , Testes de Sensibilidade Microbiana
3.
Methods Mol Biol ; 2625: 201-216, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36653645

RESUMO

Outer membrane vesicles (OMVs), also called as bacterial membrane vesicles (BMVs), are secreted by many Gram-negative bacterial pathogens. These nanoscale vesicles traffic discrete arrays of virulence factors that can often induce complex pathologies far from the infection sites. The OMVs of P. aeruginosa, often regarded as the gold standard of BMVs are known to traffic a battery of specific small MW alkyl-quinolones (AQs). These AQs function like primordial hormones by modulating intra-species and inter-species bacterial interactions. They can also perform cross-kingdom signaling with the human host and directly exacerbate pathogenesis. The discrete isotopic signatures of AQs enjoy potential in the mass spectrometry-based diagnosis P. aeruginosa infections. Matrix-free laser desorption/ionization mass spectrometry (LDI-MS) presents a robust, cost-effective platform to fit this demand. We describe a LDI-MS system using inert ceramic filters that performs dual role of single-step enrichment of OMVs and matrix-free ionization/identification of AQs in situ.


Assuntos
Quinolonas , Humanos , Pseudomonas aeruginosa , Transdução de Sinais
4.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36650020

RESUMO

BACKGROUND: Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment. METHODS: We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models. RESULTS: Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo. CONCLUSION: Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.


Assuntos
Reabsorção Óssea , Mieloma Múltiplo , Quinolonas , Animais , Camundongos , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Proliferação de Células , Imunossupressores/farmacologia , Mieloma Múltiplo/patologia , Células Mieloides/metabolismo , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Quinolonas/metabolismo , Microambiente Tumoral , Humanos
5.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675148

RESUMO

Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water-metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Acinetobacter baumannii (A. baumannii), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.


Assuntos
Quinolonas , Infecções Estafilocócicas , Humanos , DNA Girase/metabolismo , Staphylococcus aureus/metabolismo , DNA Topoisomerase IV/genética , Clivagem do DNA , Antibacterianos/farmacologia , Antibacterianos/química , Quinolonas/farmacologia , Fluoroquinolonas , Inibidores da Topoisomerase II/farmacologia , Bactérias/metabolismo , Testes de Sensibilidade Microbiana , DNA Topoisomerases Tipo II/metabolismo
6.
ACS Infect Dis ; 9(1): 150-161, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36538577

RESUMO

Pseudomonas aeruginosa (P. aeruginosa) is commonly implicated in hospital-acquired infections where its capacity to form biofilms on a variety of surfaces and the resulting enhanced antibiotic resistance seriously limit treatment choices. Because surface attachment sensitizes P. aeruginosa to quorum sensing (QS) and induces virulence through both chemical and mechanical cues, we investigate the effect of surface properties through spatially patterned mucin, combined with sub-inhibitory concentrations of tobramycin on QS and virulence factors in both mucoid and non-mucoid P. aeruginosa strains using multi-modal chemical imaging combining confocal Raman microscopy and matrix-assisted laser desorption/ionization-mass spectrometry. Samples comprise surface-adherent static biofilms at a solid-water interface, supernatant liquid, and pellicle biofilms at an air-water interface at various time points. Although the presence of a sub-inhibitory concentration of tobramycin in the supernatant retards growth and development of static biofilms independent of strain and surface mucin patterning, we observe clear differences in the behavior of mucoid and non-mucoid strains. Quinolone signals in a non-mucoid strain are induced earlier and are influenced by mucin surface patterning to a degree not exhibited in the mucoid strain. Additionally, phenazine virulence factors, such as pyocyanin, are observed in the pellicle biofilms of both mucoid and non-mucoid strains but are not detected in the static biofilms from either strain, highlighting the differences in stress response between pellicle and static biofilms. Differences between mucoid and non-mucoid strains are consistent with their strain-specific phenology, in which the mucoid strain develops highly protected biofilms.


Assuntos
Antibacterianos , Quinolonas , Antibacterianos/farmacologia , Pseudomonas aeruginosa , Quinolonas/farmacologia , Mucinas , Biofilmes , Tobramicina/farmacologia , Fatores de Virulência
7.
Eur J Med Chem ; 247: 115026, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36577217

RESUMO

The ESKAPE (Escherichia coli/E. coli, Staphylococcus aureus/S. aureus, Klebsiella pneumonia/K. pneumoniae, Acinetobacter Baumannii/A. baumannii, Pseudomonas aeroginosa/P. aeroginosa and Enterobacter spp.) pathogens, which could escape or evade common therapies through diverse antimicrobial resistance mechanisms and biofilm formation, are deemed as highly virulent bacteria responsible for life-threatening diseases, calling for novel chemotherapeutics. Quinolones including 2-quinolones and 4-quinolones have occupied a propitious place in drug design and development due to their excellent pharmacological profiles. Quinolones especially fluoroquinolones could inhibit the synthesis of nucleic acid of ESKAPE pathogens, leading to the rupture of bacterial chromosome. However, the resistance of ESKAPE pathogens to quinolones develops rapidly and spreads widely. Accordingly, it has become increasingly urgent to enhance the potency of quinolones against both drug-susceptible and drug-resistant ESKAPE pathogens. Quinolone hybrids can bind with different drug targets simultaneously and have been considered as useful prototypes to circumvent drug resistance. The purpose of this review is to summarize the current scenario (2018-present) of quinolone hybrids with potential antibacterial activity against ESKAPE pathogens, together with the structure-activity relationships and mechanisms of action to facilitate further rational design of more effective candidates.


Assuntos
Quinolonas , Staphylococcus aureus , Escherichia coli , Antibacterianos/farmacologia , Quinolonas/farmacologia , Klebsiella pneumoniae , Enterobacter
8.
PLoS One ; 17(12): e0278712, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36584044

RESUMO

The nutritional status of meat is tarnished by its association with the induced cooking contaminants. The aim of this study was to assess the heterocyclic aromatic amines profile and contents in processed chicken in Burkina Faso. Eight polar and apolar heterocyclic aromatic amines (HAAs) including 2-mino-3-methylimidazo[4,5-f]quinolone (IQ), 3-amino-1,4-dimethyl-5H-pyrido[4, 3-b]indole (Trp-P1), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P2), 2-mino-9H-pyrido-[2,3-b]indole (AαC), 2-amino-1-methyl-6-phenylimidazo[4, 5- ]pyridine (PhIP), 2-amino-3-methyl-9H-pyrido[2,3-b] indole (MeAαC), 2-amino-3,4,8-rimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) and 2-amino-3,8-imethylimidazo[4,5-]quinoxaline (MeIQx) were screened by high performance liquid chromatography from 29 samples of flamed chicken and 66 samples of braised chicken collected in Ouagadougou city. Apolar HAAs and polar HAAs were respectively 12 and 3 times more abundant in flamed chickens (32.66±10 and 3.48±10.39 ng/g, respectively) than in braised chickens (2.70±9.67 and 0.92 ng/g, respectively). The maximum levels of AαC were in the same proportions in flamed (12.01 ng/g) and braised chickens (14.13 ng/g). Flamed chicken had the highest Trp-P1 content (530.31 ng/g). The 4,8-DiMeIQx was not detected in braised chicken. The AαCs were more abundant in flamed than in braised chicken. The profile and the contents of the HAAs in processed chicken are related to cooking methods. Because of the high variability observed on the obtained concentrations, investigations on the contents of precursors in raw chicken, the effect of marinating ingredients on the formation of HAAs are needed.


Assuntos
Compostos Heterocíclicos , Quinolonas , Animais , Galinhas , Burkina Faso , Carne/análise , Aminas/análise , Culinária/métodos , Cromatografia Líquida de Alta Pressão/métodos , Quinoxalinas , Compostos Heterocíclicos/análise
9.
PLoS One ; 17(12): e0279496, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36548353

RESUMO

OBJECTIVE: To evaluate the effect of different prophylactic antibiotic treatments for cirrhosis patients with upper gastrointestinal bleeding (UGIB) and to investigate whether prophylactic antibiotics are equally beneficial to reducing the risk of adverse outcomes in A/B with low Child-Pugh scores. METHODS: Relevant studies were searched via PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Internet (CNKI), Wanfang, and VIP databases up to July 16, 2021. The heterogeneity test was conducted for each outcome measuring by I2 statistics. Subgroup analysis was performed regarding antibiotic types. Relative risk (RR) and 95% confidence interval (CI) were used to evaluate prophylactic antibiotics on the risk of adverse outcomes in cirrhosis patients with UGIB. RESULTS: Twenty-six studies involving 12,440 participants fulfilled our inclusion criteria. Antibiotic prophylaxis was associated with a reduced overall mortality (RR: 0.691, 95%CI: 0.518 to 0.923), mortality due to bacterial infections (RR: 0.329, 95%CI: 0.144 to 0.754), bacterial infections (RR: 0.389, 95%CI: 0.340 to 0.444), rebleeding (RR: 0.577, 95%CI: 0.433 to 0.767) and length of hospitalization [weighted mean difference (WMD): -3.854, 95%CI: -6.165 to -1.543] among patients with UGIB. Nevertheless, prophylactic antibiotics may not benefit to A/B population with low Child-Pugh scores. In our subgroup analysis, quinolone, beta-lactams alone or in combination reduced adverse outcomes in cirrhosis patients with UGIB. CONCLUSION: Administration of antibiotics was associated with a reduction in mortality, bacterial infections, rebleeding, and length of hospitalization. Quinolone, beta-lactams alone or in combination can be used in cirrhosis patients with UGIB. Nevertheless, targeted efforts are needed to promote the appropriate use of antibiotics among patients with cirrhosis and UGIB.


Assuntos
Infecções Bacterianas , Quinolonas , Humanos , Antibacterianos/uso terapêutico , Antibioticoprofilaxia/efeitos adversos , Infecções Bacterianas/tratamento farmacológico , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , beta-Lactamas , Hemorragia Gastrointestinal/etiologia
10.
Molecules ; 27(24)2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36557897

RESUMO

Our investigation includes the synthesis of new naphthalene-bis-triazole-bis-quinolin-2(1H)-ones 4a-e and 7a-e via Cu-catalyzed [3 + 2] cycloadditions of 4-azidoquinolin-2(1H)-ones 3a-e with 1,5-/or 1,8-bis(prop-2-yn-1-yloxy)naphthalene (2) or (6). All structures of the obtained products have been confirmed with different spectroscopic analyses. Additionally, a mild and versatile method based on copper-catalyzed [3 + 2] cycloaddition (Meldal-Sharpless reaction) was developed to tether quinolinones to O-atoms of 1,5- or 1,8-dinaphthols. The triazolo linkers could be considered as anti and syn products, which are interesting precursors for functionalized epidermal growth factor receptor (EGFR) inhibitors with potential apoptotic antiproliferative action. The antiproliferative activities of the 4a-e and 7a-e were evaluated. Compounds 4a-e and 7a-e demonstrated strong antiproliferative activity against the four tested cancer cell lines, with mean GI50 ranging from 34 nM to 134 nM compared to the reference erlotinib, which had a GI50 of 33 nM. The most potent derivatives as antiproliferative agents, compounds 4a, 4b, and 7d, were investigated for their efficacy as EGFR inhibitors, with IC50 values ranging from 64 nM to 97 nM. Compounds 4a, 4b, and 7d demonstrated potent apoptotic effects via their effects on caspases 3, 8, 9, Cytochrome C, Bax, and Bcl2. Finally, docking studies show the relevance of the free amino group of the quinoline moiety for antiproliferative action via hydrogen bond formation with essential amino acids.


Assuntos
Antineoplásicos , Quinolonas , Estrutura Molecular , Receptores ErbB/metabolismo , Proliferação de Células , Quinolonas/farmacologia , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Antineoplásicos/química , Naftalenos/farmacologia , Naftalenos/química , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais
11.
Epidemiol Infect ; 150: e205, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-36519309

RESUMO

Campylobacter spp. are one of the most common causes of bacterial gastroenteritis in Canada and worldwide. Fluoroquinolones are often used to treat complicated human campylobacteriosis and strains of Campylobacter spp. resistant to these drugs are emerging along the food chain. A scoping review was conducted to summarise how human (fluoro)quinolone-resistant (FQR; quinolones including fluoroquinolones) Campylobacter spp. infections are characterised in the literature by describing how burden of illness (BOI) associated with FQR is measured and reported, describing the variability in reporting of study characteristics, and providing a narrative review of literature that compare BOI measures of FQR Campylobacter spp. infections to those with susceptible infections. The review identified 26 studies that yielded many case reports, a lack of recent literature and a lack of Canadian data. Studies reported 26 different BOI measures and the most common were hospitalisation, diarrhoea, fever and duration of illness. There were mixed results as BOI measures reported in literature were inconsistently defined and there were limited comparisons between resistant and susceptible infections. This presents a challenge when attempting to assess the magnitude of the BOI due to FQR Campylobacter spp., highlighting the need for more research in this area.


Assuntos
Infecções por Campylobacter , Campylobacter jejuni , Campylobacter , Quinolonas , Humanos , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Canadá/epidemiologia , Infecções por Campylobacter/tratamento farmacológico , Infecções por Campylobacter/epidemiologia , Infecções por Campylobacter/microbiologia , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Efeitos Psicossociais da Doença , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana
12.
Eur J Med Res ; 27(1): 295, 2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36528637

RESUMO

BACKGROUND: The inhibitory activities of vitamins K2 against clinical isolates of quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR-MRSA) are unclear. The main aim is to better understand of inhibitory activities of vitamins K2, multi-locus sequence typing (MLST), SCCmec, and spa typing in clinical isolates of QR-MRSA on those mutation and gene expressions. MATERIALS AND METHODS: After collecting S. aureus clinical isolates and detecting QR-MRSA, the genes encoding norA, grlA, grlB, gyrA, and gyrB were sequenced. After treating isolates by vitamin K2, isolates were prepared to measure norA, grlA, grlB, gyrA, and gyrB gene expression. The quantitative-real-time PCR was used to measure the expression of efflux pump genes. RESULTS: QR-MRSA, MDR, and XDR strains were reported in 59.4%, 73.9%, and 37.6% of isolates, respectability. SCCmecIV (36.5%) and SCCmecV (26.8%) had the highest frequency. Thirty-nine spa types were identified, t021, t044, and t267 types most prevalent in QR-MRSA isolates. ST22 and ST30 dominated the invasive, drug-resistant isolates and QR-MRSA. In 24 h incubated isolates, the most noticeable change of gene expression with vitamin K2 was that the norA, gyrA, and grlB genes were highly repressed. However, the down-regulation of grlA at 24 h after being treated by vitamin K2 was more than another gene. Further, a significant decrease was observed in QR-MRSA-treated isolates compared to un-treated isolates. In other words, norA, grlA, grlB, gyrA, and gyrB genes were less suppressed by QR-MRSA (p ≤ 0.01, p ≤ 0.05). CONCLUSION: Vitamin K2 has significant inhibitory effects on the genes responsible for resistance to fluoroquinolone antibiotics. However, a subminimum inhibitory concentration (sub-MIC) level of vitamin K2 was delayed but did not completely inhibit norA, grlA, grlB, gyrA, and gyrB genes in MRSA strains.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Quinolonas , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Tipagem de Sequências Multilocus , Quinolonas/farmacologia , Vitamina K 2/farmacologia , Testes de Sensibilidade Microbiana , Vitaminas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/genética , Antibacterianos/farmacologia
13.
Zhonghua Yu Fang Yi Xue Za Zhi ; 56(12): 1745-1750, 2022 Dec 06.
Artigo em Chinês | MEDLINE | ID: mdl-36536561

RESUMO

Objective: To investigate the molecular characteristics of ciprofloxacin-cefotaxime-azithromycin co-resistant Salmonella enterica serovar Thompson (S. Thompson) isolates from sporadic cases of foodborne diseases and aquatic foods in Hunan province. Methods: Ciprofloxacin-cefotaxime-azithromycin co-resistant S. Thompson isolates were selected from samples, and broth microdilution method was used to determine the resistance to 11 antibiotics of these isolates in vitro. Whole genome sequencing was used for investigating antimicrobial resistance gene patterns and phylogenetic relationships of strains. Results: Nine ciprofloxacin-cefotaxime-azithromycin co-resistant isolates were recovered from 19 S. Thompson isolates. Among nine ciprofloxacin-cefotaxime-azithromycin co-resistant isolates, eight of them harbored IncC plasmids, simultaneously carrying plasmid-mediated quinolone resistance (PMQR) genes qepA and qnrS1, ß-lactamase resistance gene blaCMY-2, azithromycin resistance gene mph(A), and one isolate harbored IncR plasmid, and carried PMQR genes qnrB4 and aac(6')-Ib-cr, blaOXA-10 and mph(A). Genetic environment analysis showed that qnrS1, qepA, mph(A) and blaCMY-2 genes might be integrated on genomes of strains by ISKra4, IS91, IS6100 and ISEcp1, respectively. Phylogenetic core genome comparisons demonstrated that ciprofloxacin-cefotaxime-azithromycin co-resistant isolates from patients and aquatic foods were genetically similar and clustered together. Conclusion: Ciprofloxacin-cefotaxime-azithromycin co-resistant S. Thompson isolates have been isolated from both human and aquatic food samples, suggesting that the spread of multidrug resistant Salmonella between human and aquatic animals.


Assuntos
Doenças Transmitidas por Alimentos , Quinolonas , Salmonella enterica , Animais , Humanos , Ciprofloxacina , Cefotaxima , Azitromicina , Sorogrupo , Filogenia , Farmacorresistência Bacteriana Múltipla/genética , Antibacterianos/farmacologia , Salmonella , Plasmídeos , Testes de Sensibilidade Microbiana
14.
Artigo em Russo | MEDLINE | ID: mdl-36537633

RESUMO

The review is devoted to the actual problem of anti-relapse therapy for schizophrenia. The features of the use, efficiency, tolerability and safety of typical and atypical antipsychotics are discussed. The possibilities of using atypical antipsychotics of the third generation - partial dopamine receptor agonists - on the aripiprazole model are considered. According to numerous studies, aripiprazole, due to its unique pharmacological profile and combination of clinical factors, is the drug of first choice for anti-relapse supportive therapy of schizophrenia.


Assuntos
Antipsicóticos , Quinolonas , Esquizofrenia , Humanos , Aripiprazol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Antipsicóticos/uso terapêutico , Recidiva
15.
PLoS One ; 17(12): e0277692, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36574392

RESUMO

Obesity is a medical term used to describe an over-accumulation of adipose tissue. It causes abnormal physiological and pathological processes in the body. Obesity is associated with systemic inflammation and abnormalities in immune cell function. Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, has been used as a therapeutic for the protection from mucosal damage. Our previous studies have demonstrated that rebamipide treatment regulates lipid metabolism and inflammation, leading to prevention of weight gain in high-fat diet mice. In this study, mice were put on a high calorie diet for 11 weeks while receiving injections of rebamipide. Rebamipide treatment reduced the body weight, liver weight and blood glucose levels compared to control mice and reduced both glucose and insulin resistance. Fat accumulation has been shown to cause pro-inflammatory activity in mice. Treatment with rebamipide decreased the prevalence of inflammatory cells such as Th2, Th17 and M1 macrophages and increased anti-inflammatory Treg and M2 macrophages in epididymal fat tissue. Additionally, rebamipide addition inhibited adipocyte differentiation in 3T3-L1 cell lines. Taken together, our study demonstrates that rebamipide treatment is a novel and effective method to prevent diet-induced obesity.


Assuntos
Resistência à Insulina , Quinolonas , Camundongos , Animais , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Obesidade/complicações , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Quinolonas/metabolismo , Inflamação/metabolismo , Fenótipo , Dieta Hiperlipídica/efeitos adversos , Células 3T3-L1 , Camundongos Endogâmicos C57BL
16.
Molecules ; 27(23)2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36500282

RESUMO

A new dimeric prenylated quinolone alkaloid, named 2,11-didemethoxy-vepridimerine A, was isolated from the root bark of Zanthoxylum rhetsa, together with twelve known compounds. The structure of the new compound was elucidated on the basis of spectroscopic investigations (NMR and Mass). The interaction of the isolated compounds with the main protease of SARS-CoV-2 (Mpro) was evaluated using molecular docking followed by MD simulations. The result suggests that 2,11-didemethoxy-vepridimerine A, the new compound, has the highest negative binding affinity against the Mpro with a free energy of binding of -8.5 Kcal/mol, indicating interaction with the Mpro. This interaction was further validated by 100 ns MD simulation. This implies that the isolated new compound, which can be employed as a lead compound for an Mpro-targeting drug discovery program, may be able to block the action of Mpro.


Assuntos
Alcaloides , Antineoplásicos , COVID-19 , Quinolonas , Zanthoxylum , SARS-CoV-2 , Simulação de Acoplamento Molecular , Alcaloides/farmacologia , Polímeros , Inibidores de Proteases , Simulação de Dinâmica Molecular
17.
J Microbiol Methods ; 203: 106619, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36370922

RESUMO

In Neisseria gonorrhoeae, fluoroquinolone resistance is caused by mutations on various genes, especially on gyrA. Locked nucleic acid DNA sequence was added to the forward primer for gyrA and subjected to real-time quantitative polymerase chain reaction, enabling simultaneous detection of N. gonorrhoeae and mutations associated with antimicrobial resistance.


Assuntos
Gonorreia , Ácidos Nucleicos , Quinolonas , Humanos , Gonorreia/diagnóstico , Quinolonas/farmacologia , DNA Girase/genética , Mutação Puntual , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/genética , Reação em Cadeia da Polimerase em Tempo Real , Mutação , Farmacorresistência Bacteriana/genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-36360888

RESUMO

The spread of beta-lactamase-producing bacteria is of great concern and the environment has been found to be a main source of contamination. Herein, it was proposed to determine the frequency of antimicrobial-resistant-Gram-negative bacteria throughout the Lerma River basin using phenotypic and molecular methods. Resistant bacteria were isolated with chromogenic media and antimicrobial susceptibility tests were used to characterize their resistance. ARGs for beta-lactams, aminoglycosides, and quinolones were detected by PCR. Species were identified by Sanger sequencing the 16S rRNA gene and the representative genomes of MDR strains were sequenced by NGS. A high variation in the number of isolates was observed in the 20 sampled sites, while observing a low diversity among the resistant bacteria. Of the 12 identified bacterial groups, C. freundii, E. coli, and S. marcescens were more predominant. A high frequency of resistance to beta-lactams, quinolones, and aminoglycosides was evidenced, where the blaCTX,qnrB, qnrS y, and aac(6')lb-cr genes were the most prevalent. C. freundii showed the highest frequency of MDR strains. Whole genome sequencing revealed that S. marcescens and K. pneumoniae showed a high number of shared virulence and antimicrobial resistance genes, while E. coli showed the highest number of unique genes. The contamination of the Lerma River with MDR strains carrying various ARGs should raise awareness among environmental authorities to assess the risks and regulations regarding the optimal hygienic and sanitary conditions for this important river that supports economic activities in the different communities in Mexico.


Assuntos
Antibacterianos , Quinolonas , Antibacterianos/farmacologia , Rios/microbiologia , Escherichia coli , Testes de Sensibilidade Microbiana , RNA Ribossômico 16S , México , beta-Lactamases/genética , Resistência Microbiana a Medicamentos , Klebsiella pneumoniae/genética , beta-Lactamas , Aminoglicosídeos/farmacologia , Quinolonas/farmacologia , Farmacorresistência Bacteriana Múltipla/genética
19.
Clin Chest Med ; 43(4): 647-665, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36344072

RESUMO

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) corrects the underlying molecular defect causing CF disease. HEMT decreases symptom burden and improves clinical metrics and quality of life for most people with CF (PwCF) and eligible cftr mutations. Improvements in measures of pulmonary health suggest that restoration of function of defective CFTR anion channels by HEMT not only enhances airway mucociliary clearance, but also reduces chronic pulmonary infection and inflammation. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of infection and inflammation in the CF airway, and what questions remain unanswered.


Assuntos
Fibrose Cística , Quinolonas , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Fibrose Cística/tratamento farmacológico , Aminofenóis/uso terapêutico , Qualidade de Vida , Quinolonas/uso terapêutico , Mutação , Inflamação/tratamento farmacológico
20.
J Med Microbiol ; 71(11)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36346828

RESUMO

Introduction. The soaring resistance of Klebsiella pneumoniae to fluoroquinolones in PR China has substantially limited the application of these antimicrobials, especially in those clinical settings that were threatened by persistent carbapenem-resistant K. pneumoniae (CRKP), necessitating strict implementation of antimicrobial stewardship and active enhanced surveillance of infection control.Hypothesis. There is interplay between plasmid-mediated quinolone resistance (PMQR) determinants and quinolone resistance-determining region (QRDR) mutations during the acquisition of a clinically important fluoroquinolone resistance (CI-FR) profile in multidrug-resistant K. pneumoniae (MDR-KP) isolates.Aim. To investigate the high-risk CRKP clones responsible for nosocomial spread and analyse the molecular patterns of CI-FR in MDR-KP isolates in a tertiary hospital in Shanghai, PR China.Methodology. A total of 34 isolates, including 30 CRKPs, were molecularly characterized. Investigations included antimicrobial susceptibility tests, multilocus sequence typing (MLST) and wzi genotyping, PCR sequencing and phylogenetic analysis for resistance-associated genes, and clinical information retrieval from medical records.Results. Two high-risk CRKP clones, ST11-wzi64 and ST15-wzi19/wzi24, were identified as being responsible for nosocomial outbreaks in the intensive care unit (ICU) and the neurosurgery department, potentially by the respiratory route. QRDR mutations of both gyrA and parC were detected in isolates of ST15 (S83F/D87A/S80I), ST11 (S83I/D87G/S80I) and ST218 (D87A/S80I), respectively. The PMQR genes, qnrS1, aac(6')-Ib-cr and oqxAB, were present in 32 (94.1 %) of the isolates alone or in combination, co-occurring with genes (bla) encoding ß-lactamases, 16S rRNA methylases and putrescine ABC permeases. AcrR, an AcrAB transcriptional repressor, was insertion-inactivated by the IS5-like element in ST11 isolates. The encoding sequences of OmpK35 and OmpK36 genes were associated with specific STs and wzi alleles. ST11, ST15-wzi19 and ST218 isolates had frameshift disruptions in OmpK35 and specific GD insertions at position 134-135 in OmpK36. The 27 isolates with clinically important ciprofloxacin resistance (MICs ≥2 mg l-1) included 25 isolates (ST15, ST11, ST218) with multiple QRDR mutations, plus 1 with only 2 PMQR determinants (ST290-wzi21) and another with an unknown resistance mechanism (ST65-wzi72). Ciprofloxacin-susceptible isolates maintained intact ompK36 genes, including two CRKPs each with ST13-wzi74 (KPC-2 and NDM-1 coproducers) and ST65-wzi72, plus carbapenem-susceptible isolates (ST15-wzi24, ST65-wzi72, ST107-wzi173).Conclusions. Under selective pressures, the accumulation of mutations of three types (QRDR, acrR, ompK36) and the acquisition of resistance-conferring genes have continuously contributed to CI-FR in MDR-KP isolates.


Assuntos
Infecção Hospitalar , Infecções por Klebsiella , Quinolonas , Humanos , Klebsiella pneumoniae/genética , Fluoroquinolonas/farmacologia , Tipagem de Sequências Multilocus , Infecção Hospitalar/epidemiologia , RNA Ribossômico 16S , Filogenia , Antibacterianos/farmacologia , China/epidemiologia , beta-Lactamases/genética , Testes de Sensibilidade Microbiana , Carbapenêmicos , Ciprofloxacina , Surtos de Doenças , Infecções por Klebsiella/epidemiologia
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