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1.
Int J Antimicrob Agents ; 64(4): 107299, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39142419

ABSTRACT

Neisseria gonorrhoeae is a global threat to public health due to the accumulation of antimicrobial resistance mechanisms. ST-1901 is an internationally important sequence type (ST) because of its high incidence and the usual occurrence of chromosomally determined resistance. In this study, we describe the evolution of the ST-1901 and its single locus variants in Rio de Janeiro from 2006 to 2022. We analyzed 82 N. gonorrhoeae isolates according to antimicrobial susceptibility profile, resistance mechanisms, molecular typing, and phylogenetics. Six different single locus variants were detected. Phylogenetic analysis identified five clades, which share similar characteristics. Resistance rates for penicillin and tetracycline decreased due to the lower occurrence of resistance plasmids, but intermediary resistance to penicillin rose. Resistance to ciprofloxacin remained high throughout all clades and the years of the study. Regarding resistance to azithromycin, alterations in mtrR promoter and gene, and 23S rRNA encoding gene rrl were detected, with a notable rise in the incidence of C2611T mutations in more recent years occurring in four of five clades. In contrast, ß-lactam resistance associated penA 34 mosaic was found only in one persisting clade (Clade D), and unique G45D and A39T mutations in mtrR gene and its promoter (Nm-Like) were found only in Clade B. Taken together, these data suggest that ST-1901, a persistently circulating lineage of N. gonorrhoeae in Rio de Janeiro, has undergone changes over the years and may evolve to develop resistance to the current recommended dual therapy adopted in Brazil, namely, ceftriaxone and azithromycin.


Subject(s)
Anti-Bacterial Agents , Gonorrhea , Microbial Sensitivity Tests , Neisseria gonorrhoeae , Phylogeny , Neisseria gonorrhoeae/genetics , Neisseria gonorrhoeae/drug effects , Neisseria gonorrhoeae/classification , Brazil , Anti-Bacterial Agents/pharmacology , Humans , Gonorrhea/microbiology , Gonorrhea/epidemiology , Gonorrhea/drug therapy , Drug Resistance, Bacterial/genetics , Bacterial Proteins/genetics , Azithromycin/pharmacology , Ciprofloxacin/pharmacology , RNA, Ribosomal, 23S/genetics , Repressor Proteins/genetics , Plasmids/genetics , Mutation , Penicillins/pharmacology
2.
Braz J Biol ; 83: e275748, 2023.
Article in English | MEDLINE | ID: mdl-37970905

ABSTRACT

The tambaqui (Colossoma macropomum) is a species of great economic importance for fish farming in the Brazilian Amazon, and acanthocephaliasis caused by Neoechinorhynchus buttnerae (Golvan 1956) represents an obstacle to its production due to it causing severe morphological damage to the intestinal mucosa, thus impairing the absorption of nutrients and causing weight loss in the fish. Therefore, the establishment of in vitro protocols for evaluation of anthelmintic drugs is the first step to development of effective measures for in vivo control of this endoparasite. The present study evaluated the in vitro survival of N. buttnerae maintained in Eagle's minimum essential medium under different culture conditions. Three assays were carried out to evaluate whether temperature, supplementation with the antibiotics penicillin and streptomycin, and culture medium replacement or no replacement would influence the motility and morphology of the acanthocephalans. The results of the Kaplan-Meier analysis indicated that the use of culture in minimum essential medium together with penicillin and streptomycin prolonged the parasite's survival when kept at temperatures of 24 °C or 28 °C. We describe herein for first time an alternative protocol that is ideal for the in vitro culture of N. buttnerae. As such, this protocol ensures greater reliability in further in vitro studies with N. buttnerae.


Subject(s)
Acanthocephala , Characiformes , Animals , Brazil , Reproducibility of Results , Aquaculture , Intestines/parasitology , Penicillins/pharmacology , Streptomycin/pharmacology
3.
Exp Biol Med (Maywood) ; 248(19): 1657-1670, 2023 10.
Article in English | MEDLINE | ID: mdl-38030964

ABSTRACT

Bacterial cell wall formation is essential for cellular survival and morphogenesis. The peptidoglycan (PG), a heteropolymer that surrounds the bacterial membrane, is a key component of the cell wall, and its multistep biosynthetic process is an attractive antibacterial development target. Penicillin-binding proteins (PBPs) are responsible for cross-linking PG stem peptides, and their central role in bacterial cell wall synthesis has made them the target of successful antibiotics, including ß-lactams, that have been used worldwide for decades. Following the discovery of penicillin, several other compounds with antibiotic activity have been discovered and, since then, have saved millions of lives. However, since pathogens inevitably become resistant to antibiotics, the search for new active compounds is continuous. The present review highlights the ongoing development of inhibitors acting mainly in the transpeptidase domain of PBPs with potential therapeutic applications for the development of new antibiotic agents. Both the critical aspects of the strategy, design, and structure-activity relationships (SAR) are discussed, covering the main published articles over the last 10 years. Some of the molecules described display activities against main bacterial pathogens and could open avenues toward the development of new, efficient antibacterial drugs.


Subject(s)
Anti-Bacterial Agents , beta-Lactams , Penicillin-Binding Proteins/chemistry , Penicillin-Binding Proteins/metabolism , Anti-Bacterial Agents/pharmacology , beta-Lactams/chemistry , beta-Lactams/pharmacology , Penicillins/chemistry , Penicillins/metabolism , Penicillins/pharmacology , Bacteria/metabolism , Bacterial Proteins/chemistry
4.
Res Vet Sci ; 164: 105032, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37844492

ABSTRACT

Streptococcus uberis is one of the most common pathogens associated with bovine mastitis, commonly treated with antimicrobials (AM), favoring the appearance of antimicrobial resistance (AMR). The objective of this work was to determine the proportion of phenotypic AMR among S. uberis isolated worldwide from bovine intramammary infections between the years 1983-2022, and to assess the variables associated by means of a systematic review and metanalysis. Sixty articles were eligible for quantitative review. Ninety-four independent studies were obtained. The antimicrobials evaluated in more S. uberis strains were penicillin (21,987 strains), oxacillin (21,727 strains), erythromycin (20,013 strains), and ampicillin (19,354 strains). Most of the studies included in this meta-analysis were from Europe (44), followed by America (25), Africa (10), Asia (10), and Oceania (5). Among the included articles, 22 were published from 1983 to 2006, 23 from 2007 to 2012, 25 from 2013 to 2015, and the remaining 24 after 2016. Penicillin, erythromycin, and tetracycline were the antimicrobials with >25 studies. Therefore, the following analyses were performed only for these antimicrobials, presenting a high heterogeneity index (I2). The variability observed for penicillin and tetracycline was only explained, partially, by continent of origin. The variability observed for erythromycin was not explained by any of the potential explanatory variables included in this study. The S. uberis proportion of resistance to antimicrobials is highly variable and probably influenced by many factors other than those studied in this meta-analysis, where it was not possible to inform a unique average proportion of resistance.


Subject(s)
Anti-Infective Agents , Cattle Diseases , Mastitis, Bovine , Streptococcal Infections , Female , Animals , Cattle , Anti-Bacterial Agents/pharmacology , Streptococcal Infections/drug therapy , Streptococcal Infections/veterinary , Mastitis, Bovine/drug therapy , Drug Resistance, Bacterial , Microbial Sensitivity Tests/veterinary , Erythromycin/pharmacology , Tetracycline , Penicillins/pharmacology , Penicillins/therapeutic use
5.
Microb Pathog ; 180: 106129, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37119940

ABSTRACT

The increased resistance of microorganisms to antimicrobial drugs makes it necessary to search for new active compounds, such as chalcones. Their simple chemical structure makes them molecules easy to synthesize. Therefore, the aim of this study was to evaluate the antimicrobial and potentiating activity of antibiotics and antifungals by synthetic chalcones against strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and Candida tropicalis. The synthesis of chalcones was carried out by Claisen-Schimidt aldol condensation. Nuclear Magnetic Resonance (NMR) and Gas Chromatography Coupled to Mass Spectrometry (GC/MS) were also performed. Microbiological tests were performed by the broth microdilution method, using gentamicin, norfloxacin and penicillin as standard drugs for the antibacterial assay, and fluconazole for the antifungal assay. Three chalcones were obtained (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one (DB-Acetone), (1E,3E,6E,8E)-1,9-diphenylnone-1,3,6,8-tetraen-5-one (DB-CNM), (1E,4E)-1,5-bis (4-methoxyphenyl) penta-1,4-dien-3-one (DB-Anisal). The compound DB-Acetone was able to inhibit P. aeruginosa ATCC 9027 at a concentration of 1.4 × 102 µM (32 µg/mL), while DB-CNM and DB-Anisal inhibited the growth of S. aureus ATCC 25923 at 17.88 × 102 µM and 2.71 × 101 µM (512 µg/mL and 8 µg/mL) respectively. In the combined activity, DB-Anisal was able to potentiate the effect of the three antibacterial drugs tested against E. coli 06, norfloxacin (128 for 4 µg/mL ±1) against P. aeruginosa 24 and penicillin (1,024 for 16 µg/mL ±1) against S. aureus 10. In antifungal assays, chalcones were not able to inhibit the growth of fungal strains tested. However, both showed potentiating activity with fluconazole, ranging from 8.17 x 10-1 µM (0.4909 µg/mL) to 2.35 µM (13.96 µg/mL). It is concluded that synthetic chalcones have antimicrobial potential, demonstrating good intrinsic activity against fungi and bacteria, in addition to potentiating the antibiotics and antifungal tested. Further studies are needed addressing the mechanisms of action responsible for the results found in this work.


Subject(s)
Anti-Infective Agents , Chalcones , Antifungal Agents/chemistry , Fluconazole/pharmacology , Chalcones/pharmacology , Chalcones/chemistry , Staphylococcus aureus , Norfloxacin/pharmacology , Escherichia coli , Acetone/pharmacology , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Bacterial Agents/chemistry , Candida albicans , Penicillins/pharmacology , Microbial Sensitivity Tests
6.
J Mol Med (Berl) ; 101(3): 249-263, 2023 03.
Article in English | MEDLINE | ID: mdl-36688961

ABSTRACT

Previously , we demonstrated that the non-antibiotic penicillin derivative TAP7f inhibited melanoma metastasis in vitro and in vivo through the downregulation of ß-catenin and integrin αVß3. As angiogenesis is required for tumor growth and metastasis, we decided to explore the possible antiangiogenic effect of TAP7f. We found that TAP7f inhibited proliferation, migration, tube formation, and actin cytoskeleton organization of human endothelial cells. In a gel plug assay, an in vivo model for angiogenesis, TAP7f also blocked vascular formation induced by fibroblast growth factor 2. Furthermore, when murine B16-F10 melanoma cells pre-treated with TAP7f were injected intradermally in mice, we observed a decrease in the number and thickness of the capillaries surrounding the tumor. Additionally, TAP7f downregulated vascular endothelial growth factor (VEGF) and platelet-derived growth factor-B (PDGF-B) expression in B16-F10 cells and VEGF receptor expression in HMEC-1 endothelial cells. When the antitumor effect of TAP7f was studied in C57BL/6 J mice challenged with B16-F10 melanoma cells, a significant reduction of tumor growth was observed. Furthermore, a decreased expression of VEGF, PDGF-B, and the endothelial cell marker CD34 was observed in tumors from TAP7f-treated mice. Together, our results suggest that the antiangiogenic activity of TAP7f contributes to its antitumor and antimetastatic action and positions this penicillin derivative as an alternative or complementary agent for the treatment of melanoma. KEY MESSAGES: • TAP7f inhibits proliferation, migration, tube formation, and actin cytoskeleton organization of endothelial cells. • TAP7f downregulates VEGF receptor expression in endothelial cells. • TAP7f downregulates VEGF and PDGF expression in melanoma cells. • TAP7f inhibits angiogenesis in vivo.


Subject(s)
Melanoma, Experimental , Vascular Endothelial Growth Factor A , Mice , Humans , Animals , Vascular Endothelial Growth Factor A/metabolism , Endothelial Cells/metabolism , Penicillins/pharmacology , Penicillins/therapeutic use , Neovascularization, Pathologic/metabolism , Mice, Inbred C57BL , Melanoma, Experimental/drug therapy , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Cell Line, Tumor
7.
Braz J Microbiol ; 54(1): 559-563, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36525240

ABSTRACT

Caseous lymphadenitis is a well-known disease caused by Corynebacterium pseudotuberculosis affecting small ruminants with small significance to human health because of its minor zoonotic potential. In both cases, few treatment options are available and conventional antimicrobial therapy is commonly refractory due to development of pyogranulomatous reactions, bringing great interest in discovering novel therapeutics for more suitable approaches. Dideoxynucleotides presented antibacterial action against various bacteria but were never described for C. pseudotuberculosis. Hypothesizing the antimicrobial action of 2',3'-dideoxiadenosine (ddATP) against C. pseudotuberculosis, we performed for the first time an investigation of its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in the ATCC® 19,410 strain and a well-characterized clinical isolate of C. pseudotuberculosis. We also assessed potential synergism with penicillin. ddATP showed a growth delay effect for C. pseudotuberculosis at 2 µmol/mL and a MIC and MBC of 4 µmol/mL against the ATCC® 19,410 strain, but not for the clinical strain. An antimicrobial effect was observed when using concentrations lower than the MIC of ddATP associated with penicillin for both strains tested. Our data suggest the potential of nucleotide analogs, especially adenosine, and its combination with penicillin, as a possible novel treatment for C. pseudotuberculosis-induced infections, and contributes with knowledge regarding alternative drugs to treat C. pseudotuberculosis infections.


Subject(s)
Corynebacterium Infections , Corynebacterium pseudotuberculosis , Lymphadenitis , Humans , Penicillins/pharmacology , Corynebacterium Infections/microbiology , Lymphadenitis/microbiology , Anti-Bacterial Agents/pharmacology
8.
Curr Microbiol ; 79(8): 243, 2022 Jul 07.
Article in English | MEDLINE | ID: mdl-35796838

ABSTRACT

In a recent work we showed that, besides lovastatin, ROS also accumulate during the production phase in Pencillium chrysogenum and in Acremonium chrysogenum, and that these ROS regulate the biosynthesis of penicillin and cephalosporin C. In the present study, we investigated the level at which this positive regulation is exerted. Internal ROS levels were manipulated, i.e., increased or decreased, in the production phase of the respective fermentations. Penicillin production decreased by 51.2% when internal ROS concentration was diminished by 50%, while a 62% production increase was observed when ROS were increased (62%). Similarly, Cephalosporin production decreased (35%) with antioxidants and increased (54.1%) with exogenous ROS. Expression analysis of the respective pcbAB genes, encoding the non-ribosomal peptide synthetase enzymes, was performed. Results showed down regulation of these genes in fermentations with lower ROS content, and upregulation in the cultures with higher ROS content, in both species. This showed that ROS regulation of penicillin in P. chrysogenum and of cephalosporin C in A. chrysogenum, is exerted at transcriptional level. In silico analysis of the pcbAB gene promoters in both species, suggested that this regulation could be mediated by stress-response transcription factors like Yap1, SrrA and/or MsnA, and/or by the Hap complex.


Subject(s)
Cephalosporins , Penicillins , Cephalosporins/pharmacology , Gene Expression Regulation, Fungal , Penicillins/pharmacology , Reactive Oxygen Species/metabolism , Transcription Factors/genetics
9.
J Cancer Res Clin Oncol ; 148(12): 3361-3373, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35751681

ABSTRACT

PURPOSE: To investigate the effect of TAP7f, a penicillin derivative previously characterized as a potent antitumor agent that promotes ER stress and apoptosis, in combination with thapsigargin, an ER stress inducer, on melanoma cells. METHODS: The synergistic antiproliferative effect of TAP7f in combination with thapsigargin was studied in vitro in murine B16-F0 melanoma cells, and in human A375 and SB2 melanoma cells. In vivo assays were performed with C57BL/6J mice challenged with B16-F0 cells. Immunofluorescence and Western blot assays were carried out to characterize the induction of ER stress and apoptosis. Necrotic tumor areas and the potential toxicity of the combined therapy were examined by histological analysis of tissue sections after hematoxylin-eosin staining. RESULTS: In vitro, the combination of TAP7f with thapsigargin synergistically inhibited the proliferation of murine B16-F0, and human A375 and SB2 melanoma cells. When non-inhibitory doses of each drug were simultaneously administered to C57BL/6J mice challenged with B16-F0 cells, a 50% reduction in tumor volumes was obtained in the combined group. An apoptotic response characterized by higher expression levels of Baxenhanced PARP-1 cleavage and the presence of active caspase 3 was observed in tumors from the combined treatment. In addition, higher expression levels of GADD153/CHOP and ATF4 were found in tumors of mice treated with both drugs with respect to each drug used alone, indicating the induction of an ER stress response. No signs of tissue toxicity were observed in histological sections of different organs extracted from mice receiving the combination. CONCLUSION: The synergistic and effective antitumor action of TAP7f in combination with thapsigargin could be considered as a potential therapeutic strategy for melanoma treatment.


Subject(s)
Antineoplastic Agents , Melanoma , Animals , Humans , Mice , Antineoplastic Agents/pharmacology , Apoptosis , Caspase 3/metabolism , Cell Line, Tumor , Melanoma/pathology , Mice, Inbred C57BL , Penicillins/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Thapsigargin/pharmacology
10.
Microb Drug Resist ; 28(5): 517-524, 2022 May.
Article in English | MEDLINE | ID: mdl-35263182

ABSTRACT

Streptococcus agalactiae (Group B Streptococcus , GBS) is a major agent of perinatal infections. Biofilms have been associated with GBS colonization and disease, as well as with infection persistence and recurrence. Although GBS remains susceptible to beta-lactams, it is still unknown how sessile cells respond to these antibiotics. Here, we evaluated the effect of different concentrations of penicillin (3-48 mg/L) on in vitro biofilm formation by four GBS strains belonging to serotype Ia/clonal complexes23 that were recovered from the oropharynx or urine of pregnant women and were previously characterized as strong biofilm producers. All four GBS strains were fully susceptible to penicillin (minimum inhibitory concentration = 0.023 mg/L), but penicillin was not able to fully prevent biofilm formation by these GBS strains. Biofilms formed in the presence of penicillin had reduced biomasses and thickness, but they were still classified as strong. Penicillin significantly reduced the density of live cells, but higher penicillin concentrations did not lead to improved prevention of biofilm formation. Biofilms formed in the presence of penicillin had no channels or long cocci chains observed in penicillin-free biofilms. Overall, results highlight the concerning possible impacts of biofilm formation in penicillin-based treatment and preventive strategies of GBS infections, even when the bacterial strain involved is fully antibiotic-susceptible.


Subject(s)
Streptococcal Infections , Streptococcus agalactiae , Anti-Bacterial Agents/pharmacology , Biofilms , Female , Humans , Microbial Sensitivity Tests , Penicillins/pharmacology , Pregnancy , Serogroup , Streptococcal Infections/drug therapy , Streptococcal Infections/microbiology
11.
J Equine Vet Sci ; 111: 103890, 2022 04.
Article in English | MEDLINE | ID: mdl-35124153

ABSTRACT

The objectives of this study were to determine the prevalence of S. equi in a horse population in Colombia, to determine the risk factors associated with its detection in the guttural pouches and to report the antimicrobial susceptibility of the isolates. Fifteen farms and 137 horses >6 months of age were enrolled. Sampling was randomly, stratified and proportional to the population size of each farm. The guttural pouch (GP) was swabbed via endoscopic guidance and culture was performed. DNA extraction and conventional PCR were performed in colonies compatibles with S. equi, the PCR products were sequenced and subjected to BLAST analysis. Antimicrobial drug sensitivity was assessed using an antimicrobial disc diffusion assay including penicillin, ceftiofur, trimethoprim-sulfamethoxasole (TMS), enrofloxacin and oxytetracycline. A mixed logistic regression model was constructed to evaluate risk factors associated with the presence of S. equi. The S. equi culture prevalence in the GP was 15%; 13.5 % for S. equi subsp. equi and 1.5% for S. equi subsp. zooepidemicus. History of travel was associated with the presence of S. equi, whereas every 1-year increase in age decreased the risk for S. equi detection in the GP. All isolates were susceptible to TMS, ceftiofur and penicillin, but resistant to enrofloxacin and oxytetracycline. S. equi is present in horses in Colombia, with a high prevalence and appear to be endemic in the tested population. Younger horses and horses with recent history of travelling had higher odds of testing positive for S. equi in swabs of the GP.


Subject(s)
Horse Diseases , Oxytetracycline , Streptococcal Infections , Streptococcus equi , Animals , Colombia/epidemiology , Enrofloxacin , Horse Diseases/drug therapy , Horses , Penicillins/pharmacology , Prevalence , Risk Factors , Streptococcal Infections/diagnosis , Streptococcal Infections/veterinary
12.
Environ Microbiol Rep ; 14(2): 230-238, 2022 04.
Article in English | MEDLINE | ID: mdl-35060343

ABSTRACT

This study aimed to investigate whether penicillin-resistant, ampicillin-susceptible E. faecalis (PRASEF) isolates are disseminated in non-clinical sources, and to compare the molecular characteristics and antimicrobial resistance (AMR) profile of clinical and non-clinical E. faecalis isolates. Non-clinical samples (n = 280) were collected and 101 E. faecalis isolates were recovered from food (n = 18), faeces of healthy animals (n = 24), water (n = 28) and sewage (n = 31). PRASEF (n = 68) and penicillin-susceptible, ampicillin-susceptible E. faecalis (n = 77) isolates of clinical origin were also evaluated. A significant variety of AMR profiles was observed among non-clinical isolates according to the source. No food isolate exhibited a multidrug resistance (MDR) phenotype different from those of isolates from animal faeces (50.0%) and sewage (38.7%). Overall, the MDR phenotype was more frequent among clinical (56.6%) than non-clinical isolates (22.8%) (p < 0.01). Non-clinical PRASEF isolates (n = 3) were only recovered from hospital sewage. Note that representative clinical and non-clinical PRASEF isolates were grouped in pulsotype A, and belonged to CC9 (clonal complex). In conclusion, E. faecalis isolates exhibiting the unusual penicillin-resistant but ampicillin-susceptible phenotype appeared to be restricted to the hospital environment. Our findings highlight the ability of PRASEF isolates to survive in sewage, which could enable these hospital-adapted lineages to spread to new ecological niches.


Subject(s)
Enterococcus faecalis , Gram-Positive Bacterial Infections , Ampicillin/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/genetics , Gram-Positive Bacterial Infections/veterinary , Microbial Sensitivity Tests , Penicillins/pharmacology
13.
Apoptosis ; 27(1-2): 34-48, 2022 02.
Article in English | MEDLINE | ID: mdl-34773171

ABSTRACT

We have previously examined the in vitro and in vivo antitumor action of TAP7f, a synthetic triazolylpeptidyl penicillin, on murine melanoma cells. In this work, we explored the signal transduction pathways modulated by TAP7f in murine B16-F0 and human A375 melanoma cells, and the contribution of some intracellular signals to the apoptotic cell death. TAP7f decreased ERK1/2 phosphorylation and increased phospho-p38, phospho-JNK and phospho-Akt levels. ERK1/2 blockage suppressed cell growth, while inhibition of p38, JNK and PI3K-I pathways reduced the antitumor effect of TAP7f. Pharmacological inhibition of p38 and JNK, or blockage of PI3K-I/Akt cascade with a dominant negative PI3K-I mutant diminished Bax expression levels and PARP-1 cleavage, indicating the involvement of these pathways in apoptosis. PI3K-I/Akt inhibition also favored an autophagic response, as evidenced by the higher expression levels of Beclin-1 and LC3-II detected in transfected cells exposed to TAP7f. However, although PI3K-I/Akt blockage promoted an autophagic survival response, this mechanism appears not to be critical for TAP7f antitumor action. It was also shown that TAP7f induced ER stress by enhancing the expression of ER stress-related genes and proteins. Downregulation of CHOP protein with specific siRNA increased cell growth and decreased cleavage of PARP-1, supporting its role in apoptosis. Furthermore, it was found that activation of p38, JNK and Akt occurred downstream ER perturbation. In summary, our results showed that TAP7f triggers an apoptotic cell death in melanoma cells through induction of ER stress and activation of p38, JNK and PI3K-I/Akt pathways.


Subject(s)
Endoplasmic Reticulum Stress , Melanoma , Animals , Apoptosis , Humans , Melanoma/drug therapy , Melanoma/genetics , Mice , Penicillins/pharmacology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism
14.
Future Med Chem ; 13(13): 1127-1139, 2021 07.
Article in English | MEDLINE | ID: mdl-33998275

ABSTRACT

Aim: Encouraged by the antitumor activity exhibited by triazolylpeptidyl penicillins, we decided to synthesize and evaluate a library of peptoid analogs. Results: The replacement of the dipeptide unit of the reference compound, TAP7f, was investigated. In addition, the effect of the triazole linking group on the biological activity of these new derivatives was evaluated, exchanging it with a glycine spacer. The cytotoxic effect of the library compounds was determined in the B16-F0 cell line and compared with the effects on normal murine mammary gland cells. Conclusion: Among the tested compounds, peptoid 4e exhibited the highest antiproliferative activity.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Penicillins/pharmacology , Peptoids/pharmacology , Triazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Mice , Molecular Conformation , Penicillins/chemical synthesis , Penicillins/chemistry , Peptoids/chemical synthesis , Peptoids/chemistry , Triazoles/chemical synthesis , Triazoles/chemistry , Tumor Cells, Cultured
15.
Ann Clin Microbiol Antimicrob ; 19(1): 43, 2020 Sep 17.
Article in English | MEDLINE | ID: mdl-32943051

ABSTRACT

This study aimed to evaluate the accuracy of disk diffusion and Etest methods, compared to that of the broth dilution reference method for identifying beta-lactam susceptibilities of Penicillin-Resistant, Ampicillin-Susceptible Enterococcus faecalis (PRASEF) isolates. Fifty-nine PRASEF and 15 Penicillin-Susceptible, Ampicillin-Susceptible E. faecalis (PSASEF) clinical nonrepetitive isolates were evaluated. The effectiveness of five beta-lactams (ampicillin, amoxicillin, imipenem, penicillin, and piperacillin) was tested. All antimicrobial susceptibility tests were performed and interpreted according to the Clinical and Laboratory Standards Institute guidelines. Interpretative discrepancies, such as essential agreement, categorical agreement, and errors, were assessed. The acceptability was ≥ 90% for both categorical agreement and essential agreement. Etest proved to be an accurate method for testing beta-lactam susceptibilities of the emerging PRASEF isolates, disk diffusion presented poor performance, particularly for imipenem and piperacillin.


Subject(s)
Disk Diffusion Antimicrobial Tests/methods , Enterococcus faecalis/drug effects , Microbial Sensitivity Tests/methods , beta-Lactams/pharmacology , Amoxicillin/pharmacology , Ampicillin/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial , Humans , Imipenem/pharmacology , Penicillins/pharmacology , Piperacillin/pharmacology , Sensitivity and Specificity
16.
In. Giachetto Larraz, Gustavo A; Pardo Casaretto, Lorena Victoria; Speranza Mourine, María Noelia. Prescripción de antimicrobianos para infecciones frecuentes en pediatría. Montevideo, Bibliomédica, 2020. p.53-89, ilus, tab.
Monography in Spanish | LILACS, UY-BNMED, BNUY | ID: biblio-1373293
17.
Microb Pathog ; 136: 103652, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31398534

ABSTRACT

The aim of this study was to determine the effect of fibronectin and laminin on the in vitro biofilm formation by Streptococcus uberis and the susceptibility to penicillin under planktonic and biofilm growth conditions. We observed that a high percentage (76.5%) of the S. uberis isolates was weak biofilm producers in Todd Hewitt Broth (THB). A high percentage of moderate (38.2%) or strong (53%) biofilm producers was observed in THB supplemented with laminin or fibronectin, respectively. All S. uberis isolates growing as planktonic cells were sensitive to penicillin. Minimum biofilm inhibitory concentrations (MBICs) were ranging between 0.25 and 2 µg/ml, whereas minimum biofilm eradication concentrations (MBECs) ranging from 8 to 256 µg/ml. These results show that biofilm-growing S. uberis cells required higher concentrations of the antibiotic than those needed to inhibit planktonic cells. Similar MBICs of penicillin were obtained when S. uberis cells growing in THB supplemented or not with laminin or fibronectin, whereas the MBECs markedly increased when one of two proteins were added to culture medium compared with the medium without proteins. To the best of our knowledge, this is the first report of decreased susceptibility to penicillin likely related to a higher production of biofilms stimulated by laminin or fibronectin. Therapeutic failures of penicillin to treat S. uberis infections may be due to biofilm formation.


Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Drug Tolerance , Fibronectins/metabolism , Laminin/metabolism , Penicillins/pharmacology , Streptococcus/drug effects , Biofilms/growth & development , Culture Media/chemistry , Microbial Sensitivity Tests , Streptococcus/growth & development
18.
Microb Drug Resist ; 25(9): 1275-1281, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31361553

ABSTRACT

Objectives: This study aimed to characterize the molecular mechanism of resistance to gentamicin among penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) isolates by investigating the presence of the aac(6')-Ie-aph(2'')-Ia gene. The co-resistance to antimicrobials of other classes was also evaluated. Results: Among the 151 isolates evaluated, 70 were PRASEF and 81 were penicillin-susceptible and ampicillin-susceptible E. faecalis (PSASEF). No ß-lactamase producing isolate was detected. Eighty-three (55.0%) and 35 (23.2%) out of the 151 E. faecalis isolates showed high-level gentamicin resistance (HLGR) and high-level streptomycin resistance (HLSR) phenotypes. However, a significantly higher rate of PRASEF (88.6%) showed HLGR phenotype in comparison with PSASEF (23.5%) (p < 0.01). Conversely, a significantly lower rate of PRASEF (14.3%) showing HLSR was observed in comparison with PSASEF (30.9%) (p = 0.02). The prevalence of isolates displaying multidrug resistance (MDR) phenotype was significantly higher (p < 0.01) in the group of PRASEF (81.4%) than in PSASEF (18.6%). The majority of PSASEF (61.9%) and PRASEF (90.3%) isolates showing HLGR phenotype was harboring the aac(6')-Ie-aph(2'')-Ia gene, which encodes a bifunctional enzyme that inactivates all aminoglycosides except streptomycin. Conclusion: The aac(6')-Ie-aph(2'')-Ia gene was prevalent among the Brazilian PRASEF isolates that usually exhibit co-resistance to gentamicin and to multiple other drugs.


Subject(s)
Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Gentamicins/pharmacology , Gram-Positive Bacterial Infections/drug therapy , Penicillins/pharmacology , Acetyltransferases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Brazil , Child , Child, Preschool , Drug Resistance, Multiple, Bacterial , Enterococcus faecalis/genetics , Enterococcus faecalis/isolation & purification , Female , Gentamicins/administration & dosage , Gram-Positive Bacterial Infections/microbiology , Hospitals , Humans , Infant , Infant, Newborn , Male , Microbial Sensitivity Tests , Middle Aged , Penicillins/administration & dosage , Phosphotransferases (Alcohol Group Acceptor)/genetics , Prevalence , Young Adult
19.
Vaccine ; 36(32 Pt B): 4861-4874, 2018 08 06.
Article in English | MEDLINE | ID: mdl-30005949

ABSTRACT

BACKGROUND: This systematic review aims to describe the prevalence, trends, and antibiotic resistance of Streptococcus pneumoniae serotype 19A (Spn19A) that causes invasive and non-invasive diseases in children <5 years in Latin-American and Caribbean countries. METHODS: We searched for published (between January 2010 and February 2016) observational and clinical studies within the region including effectiveness and impact on Spn19A after pneumococcal conjugate vaccine (PCV) introduction. We calculated prevalence estimates by country and standardized the frequency of isolates to conduct an interrupted time series analysis for selected countries and to assess the potential changes in disease trends, overall and for Spn19A. RESULTS: We identified and reviewed full-text of 89 publications and included 59 in the analysis. Data from the laboratory surveillance network, SIREVA, were included in 43 (74%) of the invasive pneumococcal disease reports. There are differences in the sensitivity, representativeness, and heterogeneity of laboratory surveillance. There has been and overall reduction in the trend and number of invasive S. pneumoniae isolates in children <5 years after PCVs introduction. To date, the prevalence of Spn19A has increased, however, there has been no observed change in the trend. CONCLUSIONS: This updated systematic review provides evidence of a reduction in the total number of invasive pneumococcal disease isolates after the introduction of PCVs in the region but cannot yet conclude a change in the trend of Spn19A disease.


Subject(s)
Pneumococcal Infections/immunology , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines/therapeutic use , Streptococcus pneumoniae/pathogenicity , Vaccines, Conjugate/therapeutic use , Caribbean Region , Humans , Latin America , Penicillins/pharmacology , Pneumococcal Infections/drug therapy , Serogroup , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/immunology
20.
Braz. j. microbiol ; Braz. j. microbiol;49(1): 5-6, Jan.-Mar. 2018.
Article in English | LILACS | ID: biblio-889197

ABSTRACT

ABSTRACT The type strain SUR2 of the novel species Chryseobacterium limigenitum was isolated from a dehydrated sludge of the municipal sewage treatment plant in Dogoše near Maribor in Slovenia. The draft genome, with 60 contigs, 4,697,725 bp, 34.4% of G+C content, was obtained using the Illumina HiSeq 2500-1 platform. Joint Genome Institute Microbial Genome Annotation Pipeline (MGAP v.4) has identified 4322 protein-coding sequences including resistance genes against arsenic and other heavy metals. In addition, a subclass B3 metallo-β-lactamase, which confers resistance to penicillins, cephalosporins and carbapenems, was also present in the genome. The genome sequence provides important information regarding bioremediation potential and pathogenic properties of this newly identified species.


Subject(s)
Sewage/microbiology , Genome, Bacterial , Chryseobacterium/genetics , Penicillins/pharmacology , Phylogeny , Sewage/chemistry , Base Composition , DNA, Bacterial/genetics , Molecular Sequence Data , Base Sequence , Microbial Sensitivity Tests , Carbapenems/pharmacology , Chryseobacterium/isolation & purification , Chryseobacterium/classification , Chryseobacterium/drug effects , Anti-Bacterial Agents/pharmacology
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