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Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.

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We identified a chromosomal qnrB19 gene within a transposon in a colistin-resistant Escherichia coli strain isolated from the stool sample of an Ecuadorian resident. This finding suggests a more stable acquisition of quinolone resistance on chromosomes than that on plasmids and the potential for propagation to other DNA structures.

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Introdução: As quinolonas, amplamente usadas na prática clínica, correspondem à segunda causa de reações de hipersensibilidade aos antibióticos. Reações às quinolonas (RQ) são um desafio para o alergista, pois ocorrem por mecanismos IgE mediados, mas também por uma via não imunológica, o receptor MRGPRX2. Objetivo: Este trabalho avalia a reatividade cutânea de pessoas sem alergia ao ciprofloxacino em diversas concentrações. Metodologia: Foram realizados prick tests (PT) e testes intradérmicos de leitura imediata (ID) com ciprofloxacino em voluntários atendidos em um ambulatório de serviço terciário. No PT, foram usadas concentrações de 2 mg/mL (solução mãe), 1:10 e 1:50. No ID, 1:10, 1:50, 1:100 e 1:500. Resultados: Foram incluídos 31 indivíduos sem histórico de RQ. A média de idade foi de 40,5 anos, sendo 74,1% do gênero feminino. Doenças atópicas foram encontradas em 48,4% dos participantes, 100% destes com rinite alérgica, 20% com conjuntivite alérgica, 13,3% com asma, e 13,3% com dermatite atópica. Uso prévio de quinolonas foi relatado por 45,2% dos indivíduos. O PT puro e 1:10 foi positivo em 25,8% e 6,5%, respectivamente; na concentração 1:50 não mostrou positividade. O ID 1:10, 1:50 e 1:100 foi positivo em 96,8%, 45,2% e 6,5%, respectivamente, mas foi negativo na diluição 1:500. Nos que já usaram quinolonas, o PT puro e 1:50 foram positivos em 28,6% e 14,3% dos participantes, respectivamente, versus 25% e 0% nos que não usaram. O ID entre os indivíduos que já usaram foi positivo em 100% na diluição 1:10, 57,1% na 1:50, e 14,3% na 1:100. Entre os que não usaram, 93,7% na diluição 1:10, 37,6% na 1:50, e 0% na 1:100. Nos atópicos, o PT foi positivo em 26,7% e 13,3% na concentração mãe e 1:10; e negativo em 1:50. Nos participantes não atópicos, observou-se positividade de 25% no PT com a solução mãe e testes negativos nas demais diluições. O ID com as soluções 1:10, 1:50 e 1:100 foi positivo em 100%, 46,7% e 6,7% dos atópicos, e 93,7%, 43,7%, 6,3% nos não atópicos, respectivamente. Conclusão: O ciprofloxacino apresenta reatividade cutânea através de vias imunológicas e pelo MRGPRX2, sendo recomendada a realização de testes cutâneos em concentrações igual ou menores de 0,02 mg/ mL para investigação de reações de hipersensibilidade imediata, pois essas concentrações apresentam boa especificidade.

Introduction: Quinolones, widely used in clinical practice, are the second leading cause of antibiotic hypersensitivity. Hypersensitivity to quinolone poses a challenge for allergists, as it occurs through immunoglobulin E (IgE)-mediated mechanisms as well as nonimmunologic ones (specifically the MRGPRX2 receptor). Objective: To assess cutaneous hypersensitivity to ciprofloxacin at different concentrations. Methodology: Skin prick test (SPT) and immediate-reading intradermal test (IDT) with ciprofloxacin were performed on volunteers treated at a tertiary outpatient clinic. Concentrations of 2 mg/mL (main solution), 1:10, and 1:50 were used for the SPT, and concentrations of 1:10, 1:50, 1:100, and 1:500 were used for the IDT. Results: Thirty-one individuals with no history of hypersensitivity to quinolone were included, of whom 74.1% were women. Mean patient age was 40.5 years. Atopic diseases were found in 48.4% of participants, of whom 100% had allergic rhinitis, 20% had allergic conjunctivitis, 13.3% had asthma, and 13.3% had atopic dermatitis. Previous quinolone use was reported by 45.2%. SPT performed with the main solution and 1:10 dilution was positive in 25.8% and 6.5% of cases, respectively, whereas SPT with 1:50 dilution was negative in all cases. IDT performed with 1:10, 1:50, and 1:100 dilutions was positive in 96.8%, 45.2%, and 6.5% of cases, respectively, but negative with 1:500. Among the individuals who had used quinolones, SPT with main solution and 1:50 dilution was positive in 28.6% and 14.3% of cases, respectively, compared with 25% and 0% in those who had not used quinolones. Among those who had used quinolones, IDT results were positive in 100% at 1:10, 57.1% at 1:50, and 14.3% at 1:100. Among those who had not used quinolones, IDT results were positive in 93.7% at 1:10, 37.6% at 1:50, and 0% at 1:100. In atopic individuals, SPT was positive in 26.7% with the main solution and 1:10 dilution, and negative with 1:50. Among nonatopic individuals, 25% had a positive SPT with the main solution, and the remaining individuals were negative. IDT results with 1:10, 1:50, and 1:100 dilutions were positive, respectively, in 100%, 46.7%, and 6.7% of atopic individuals and in 93.7%, 43.7%, and 6.3% of nonatopic individuals. Conclusion: Ciprofloxacin triggers cutaneous hypersensitivity via immunologic mechanisms and the MRGPRX2 receptor. It is recommended that skin tests be performed at a dilution of 1:100 or greater to investigate immediate hypersensitivity.

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Quinolone resistance has been largely related to the presence of specific point mutations in chromosomal targets, with an accessory role of impaired uptake and enhanced pump-out. Meanwhile the relevance of transferable mechanisms of resistance able to protect the target of pump-out or inactivate quinolones has been increasingly reported since 1998. Nevertheless, bacteria have other strategies and mechanisms allowing them to survive and even proliferate in the presence of quinolones, which might be qualified as resistance or resilience mechanisms. These include decreasing levels of quinolone target production, transient amoeba protection, benthonic lifestyle, nutrient-independent slow growth, activation of stringent response, inactivation or degradation of quinolones as well as apparently unrelated or forgotten chromosomal mutations. These mechanisms have been largely overlooked, either because of the use of classical approaches to antibiotic resistance determination or due to the low increase in final minimum inhibitory concentration levels. This article is devoted to a review of a series of these mechanisms.

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Pluralibacter gergoviae is a member of the Enterobacteriaceae family that has been reported sporadically. Although P. gergoviae strains exhibiting multidrug-resistant profiles have been identified an in-depth genomic analysis focusing on antimicrobial resistance (AMR) has been lacking, and was therefore performed in this study. Forty-eight P. gergoviae strains, isolated from humans, animals, foods, and the environment during 1970-2023, were analyzed. A large number of single-nucleotide polymorphisms were found, indicating a highly diverse population. Whilst P. gergoviae strains were found to be circulating at the One Health interface, only human and environmental strains exhibited multidrug resistance genotypes. Sixty-one different antimicrobial resistance genes (ARGs) were identified, highlighting genes encoding mobile colistin resistance, carbapenemases, and extended-spectrum ß-lactamases. Worryingly, the co-occurrence of mcr-9.1, blaKPC-2, blaCTX-M-9, and blaSHV-12, as well as mcr-10.1, blaNDM-5, and blaSHV-7, was detected. Plasmid sequences were identified as carrying clinically important ARGs, evidencing IncX3 plasmids harboring blaKPC-2, blaNDM-5, or blaSHV-12 genes. Virulence genotyping underlined P. gergoviae as being a low-virulence species. In this regard, P. gergoviae is emerging as a new multidrug-resistant species belonging to the Enterobacteriaceae family. Therefore, continuous epidemiological genomic surveillance of P. gergoviae is required.

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Salmonella Isangi is an infrequent serovar that has recently been reported in several countries due to nosocomial infections. A considerable number of reports indicate Salmonella Isangi multidrug resistance, especially to cephalosporins, which could potentially pose a risk to public health worldwide. Genomic analysis is an excellent tool for monitoring the emergence of microorganisms and related factors. In this context, the aim of this study was to carry out a genomic analysis of Salmonella Isangi isolated from poultry in Brazil, and to compare it with the available genomes from the Pathogen Detection database and Sequence Read Archive. A total of 142 genomes isolated from 11 different countries were investigated. A broad distribution of extended-spectrum beta-lactamase (ESBL) genes was identified in the Salmonella Isangi genomes examined (blaCTX-M-15, blaCTX-M-2, blaDHA-1, blaNDM-1, blaOXA-10, blaOXA-1, blaOXA-48, blaSCO-1, blaSHV-5, blaTEM-131, blaTEM-1B), primarily in South Africa. Resistome analysis revealed predicted resistance to aminoglycoside, sulfonamide, macrolide, tetracycline, trimethoprim, phenicol, chloramphenicol, and quaternary ammonium. Additionally, PMQR (plasmid-mediated quinolone resistance) genes qnr19, qnrB1, and qnrS1 were identified, along with point mutations in the genes gyrAD87N, gyrAS83F, and gyrBS464F, which confer resistance to ciprofloxacin and nalidixic acid. With regard to plasmids, we identified 17 different incompatibility groups, including IncC, Col(pHAD28), IncHI2, IncHI2A, IncM2, ColpVC, Col(Ye4449), Col156, IncR, IncI1(Alpha), IncFIB (pTU3), Col(B5512), IncQ1, IncL, IncN, IncFIB(pHCM2), and IncFIB (pN55391). Phylogenetic analysis revealed five clusters grouped by sequence type and antimicrobial gene distribution. The study highlights the need for monitoring rare serovars that may become emergent due to multidrug resistance.

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We characterized the distribution and diversity of antimicrobial-resistance Salmonella enterica isolated from a poultry production chain in Minas Gerais, Brazil, with special attention to ciprofloxacin and multidrug resistance (MDR). S. enterica (n = 96) of different serotypes and from different processing steps were subjected to broth dilution assay to estimate the minimum inhibitory concentration (MIC) for 12 antibiotics (8 classes) and screened using PCR for the presence of 17 antimicrobial-resistance genes. Isolates presented mainly resistance to ampicillin (11/96), and most presented intermediate resistance to ciprofloxacin (92/96). Roughly one-third (33/96) were resistant to streptomycin based on our interpretive criteria. Most strains resistant to streptomycin and ciprofloxacin were PCR-positive for aphA (51/96) and qnrB (94/96), respectively. Ciprofloxacin resistance was further investigated through high-resolution melting qPCR (HRM-qPCR) and sequencing of quinolone resistance-determining region (QRDR: gyrA, gyrB, parC, and parE). Minor differences were identified in melting temperatures (Tm), and a Thr57Sr mutation was observed in parC. MDR isolates harboring acrA and capable of expressing the AcrAB-TolC multidrug efflux pump were resistant to ethidium bromide at 0.4 mg/mL. The intermediate resistance to ciprofloxacin may be associated with qnrB, and the potential role of Thr57Ser mutation warrants further investigation. The high prevalence of antibiotic related genes and its association with the observed intermediary resistance to ciprofloxacin indicates the widespread of this hazard in the studied poultry production chain.

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The presence of crpP was established in 201 Pseudomonas aeruginosa isolates from 9 Peruvian hospitals. The 76.6% (154/201) of the isolates presented the crpP gene. Overall, 123/201 (61.2%) isolates were non-susceptible to ciprofloxacin. The prevalence of crpP-possessing P. aeruginosa in Peru is higher than in other geographical areas.

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Prion Diseases or Transmissible Spongiform Encephalopathies are neurodegenerative conditions associated with a long incubation period and progressive clinical evolution, leading to death. Their pathogenesis is characterized by conformational changes of the cellular prion protein-PrPC-in its infectious isoform-PrPSc-which can form polymeric aggregates that precipitate in brain tissues. Currently, there are no effective treatments for these diseases. The 2,5-diamino-1,4-benzoquinone structure is associated with an anti-prion profile and, considering the biodynamic properties associated with 4-quinolones, in this work, 6-amino-4-quinolones derivatives and their respective benzoquinone dimeric hybrids were synthesized and had their bioactive profile evaluated through their ability to prevent prion conversion. Two hybrids, namely, 2,5-dichloro-3,6-bis((3-carboxy-1-pentyl-4-quinolone-6-yl)amino)-1,4-benzoquinone (8e) and 2,5-dichloro-3,6-bis((1-benzyl-3-carboxy-4-quinolone-6-yl)amino)-1,4-benzoquinone (8f), stood out for their prion conversion inhibition ability, affecting the fibrillation process in both the kinetics-with a shortening of the lag phase-and thermodynamics and their ability to inhibit the formation of protein aggregates without significant cytotoxicity at ten micromolar.

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OBJECTIVES: In contrast to other qnr families, qnrVC has been reported mainly in Vibrio spp. and inserted in class 1 integrons. This study aimed to identify the variants of qnrVC genes detected in Klebsiella pneumoniae carbapenemase-2-producing Enterobacter and Klebsiella strains isolated from Brazilian coastal waters and the genetic contexts associated with their occurrence. METHODS: qnrVC variants were identified by Sanger sequencing. Stains were typified by pulsed-field gel electrophoresis. Antimicrobial susceptibility testing, conjugation assays, and whole genome sequencing (WGS) were applied to identify the strains' antimicrobial resistance profile, qnrVC and blaKPC-2 co-transference, and qnrVC genetic context. RESULTS: qnrVC1 was identified in 15 Enterobacter and 3 Klebsiella, and qnrVC4 in 2 Enterobacter strains. Pulsed-field gel electrophoresis revealed 12 clonal profiles of Enterobacter and one of Klebsiella. Strains were resistant to aminoglycosides, beta-lactams, fosfomycin, quinolones, and sulfamethoxazole-trimethoprim. Co-transference of qnrVC and blaKPC-2 were obtained from five representative Enterobacter strains, which showed resistance to ampicillin and amoxicillin-clavulanate, and reduced susceptibility to extended-spectrum cephalosporins, meropenem, and ciprofloxacin. WGS analysis from representative strains revealed one K. quasipneumoniae subsp. similipneumoniae, one E. soli, four E. kobei, and seven isolates belonging to Enterobacter Taxon 3. Long-read WGS showed qnrVC and blaKPC-2 were carried by the same replicon on Klebsiella and Enterobacter strains, and the qnrVC association with not previously described genetic environments composed of insertion sequences and truncated genes. These contexts occurred in small- and high-molecular-weight plasmids belonging to IncFII, IncP6, pKPC-CAV1321, and IncU groups. CONCLUSION: Our results suggest that the dissemination of qnrVC among Enterobacterales in Brazilian coastal waters is associated with several genetic recombination events.

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