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1.
Food Chem ; 339: 127580, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858380

RESUMO

In this study, a microbiological inhibition method for rapidly screening antibiotics in swine urine was established with an easy sample pre-treatment. The microbiological system consisted of an agar medium mixed with nutrients, sensitizers, a test bacterium (Geobacillus stearothermophilus ATCC12980) and pH indicator (bromocresol purple). It was observed that the detection limits of the test kit for twenty-eight common antimicrobial residues in urine, including ß-lactams, aminoglycosides, tetracyclines, sulfonamides, macrolides, and lincosamides, were less than or equal to the maximum residue limits of the kidney, as determined by the EU and China. Moreover, the false negative rate and the false positive rate, along with other performance indexes such as interassay coefficients of variation and shelf life of the kit, all met the standard requirements of the ISO13969:2003 guidelines. Additionally, our results were consistent with those using the gold-standard physical chemistry method, which suggest the proposed method is suitable for screening antibiotic residues.


Assuntos
Antibacterianos/urina , Resíduos de Drogas/análise , Ensaios de Triagem em Larga Escala/métodos , Drogas Veterinárias/urina , Aminoglicosídeos/farmacologia , Aminoglicosídeos/urina , Animais , Antibacterianos/análise , Antibacterianos/farmacologia , Meios de Cultura , Reações Falso-Negativas , Reações Falso-Positivas , Contaminação de Alimentos/análise , Geobacillus stearothermophilus/efeitos dos fármacos , Limite de Detecção , Macrolídeos/farmacologia , Macrolídeos/urina , Sensibilidade e Especificidade , Sulfonamidas/farmacologia , Sulfonamidas/urina , Suínos , Tetraciclinas/farmacologia , Tetraciclinas/urina , Drogas Veterinárias/farmacologia
2.
Proc Natl Acad Sci U S A ; 117(34): 20530-20537, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32817463

RESUMO

Sarecycline is a new narrow-spectrum tetracycline-class antibiotic approved for the treatment of acne vulgaris. Tetracyclines share a common four-ring naphthacene core and inhibit protein synthesis by interacting with the 70S bacterial ribosome. Sarecycline is distinguished chemically from other tetracyclines because it has a 7-[[methoxy(methyl)amino]methyl] group attached at the C7 position of ring D. To investigate the functional role of this C7 moiety, we determined the X-ray crystal structure of sarecycline bound to the Thermus thermophilus 70S ribosome. Our 2.8-Å resolution structure revealed that sarecycline binds at the canonical tetracycline binding site located in the decoding center of the small ribosomal subunit. Importantly, unlike other tetracyclines, the unique C7 extension of sarecycline extends into the messenger RNA (mRNA) channel to form a direct interaction with the A-site codon to possibly interfere with mRNA movement through the channel and/or disrupt A-site codon-anticodon interaction. Based on our biochemical studies, sarecycline appears to be a more potent initiation inhibitor compared to other tetracyclines, possibly due to drug interactions with the mRNA, thereby blocking accommodation of the first aminoacyl transfer RNA (tRNA) into the A site. Overall, our structural and biochemical findings rationalize the role of the unique C7 moiety of sarecycline in antibiotic action.


Assuntos
Antibacterianos/farmacologia , Ribossomos/efeitos dos fármacos , Tetraciclinas/farmacologia , Antibacterianos/química , RNA Ribossômico 16S/química , Tetraciclinas/química , Thermus thermophilus
3.
Nat Commun ; 11(1): 3834, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737309

RESUMO

The transcriptional inducer anhydrotetracycline (aTc) and the bacteriostatic antibiotic tetracycline (Tc) are commonly used in all fields of biology for control of transcription or translation. A drawback of these and other small molecule inducers is the difficulty of their removal from cell cultures, limiting their application for dynamic control. Here, we describe a simple method to overcome this limitation, and show that the natural photosensitivity of aTc/Tc can be exploited to turn them into highly predictable optogenetic transcriptional- and growth-regulators. This new optogenetic class uniquely features both dynamic and setpoint control which act via population-memory adjustable through opto-chemical modulation. We demonstrate this method by applying it for dynamic gene expression control and for enhancing the performance of an existing optogenetic system. We then expand the utility of the aTc system by constructing a new chemical bandpass filter that increases its aTc response range. The simplicity of our method enables scientists and biotechnologists to use their existing systems employing aTc/Tc for dynamic optogenetic experiments without genetic modification.


Assuntos
Escherichia coli/efeitos dos fármacos , Optogenética/métodos , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Tetraciclina/farmacologia , Tetraciclinas/farmacologia , Transcrição Genética/efeitos dos fármacos , Clonagem Molecular , Relação Dose-Resposta a Droga , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Genes Reporter , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Fotólise , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Raios Ultravioleta
4.
Life Sci ; 257: 118080, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32653520

RESUMO

The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (Mpro). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 Mpro crystal structure. Molecular docking simulation predicted the docking score >-7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 Mpro. The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 Mpro which can used in combinational therapy against SARS-CoV-2 infection.


Assuntos
Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Tetraciclinas/farmacologia , Antibacterianos , Antivirais/farmacologia , Sítios de Ligação/fisiologia , Biologia Computacional/métodos , Infecções por Coronavirus/tratamento farmacológico , Bases de Dados Genéticas , Humanos , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Pandemias , Peptídeo Hidrolases/efeitos dos fármacos , Peptídeo Hidrolases/farmacologia , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases , Ligação Proteica/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores
5.
Diagn Microbiol Infect Dis ; 97(3): 115054, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32376058

RESUMO

Omadacycline and tigecycline MIC90 values were 2 µg/mL and 0.25 µg/mL, respectively, against Staphylococcus aureus carrying tet(M), whereas the minocycline, tetracycline, and doxycycline values were > 8 µg/mL. Similarly, omadacycline and tigecycline remained active against Enterococcus faecalis and Streptococcus pneumoniae harboring tet(L)and/or tet(M)(MIC90, 0.06-0.25 µg/mL), whereas other tetracyclines were inactive (MIC90, >8 µg/mL). Omadacycline and tigecycline remained more potent than minocycline, tetracycline, and doxycycline against Enterobacteriaceae carrying tet. This study demonstrates the effectiveness of modern tetracyclines, omadacycline, and tigecycline against isolates with tetracycline resistance genes.


Assuntos
Antibacterianos/farmacologia , Resistência a Tetraciclina/efeitos dos fármacos , Tetraciclinas/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Proteínas de Bactérias/genética , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Resistência a Tetraciclina/genética , Tigeciclina/farmacologia
6.
PLoS One ; 15(4): e0230711, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240193

RESUMO

Vaccinia virus (VACV) has been used extensively as the vaccine against smallpox and as a viral vector for the development of recombinant vaccines and cancer therapies. Replication-competent, non-attenuated VACVs induce strong, long-lived humoral and cell-mediated immune responses and can be effective oncolytic vectors. However, complications from uncontrolled VACV replication in vaccinees and their close contacts can be severe, particularly in individuals with predisposing conditions. In an effort to develop replication-competent VACV vectors with improved safety, we placed VACV late genes encoding core or virion morphogenesis proteins under the control of tet operon elements to regulate their expression with tetracycline antibiotics. These replication-inducible VACVs would only express the selected genes in the presence of tetracyclines. VACVs inducibly expressing the A3L or A6L genes replicated indistinguishably from wild-type VACV in the presence of tetracyclines, whereas there was no evidence of replication in the absence of antibiotics. These outcomes were reflected in mice, where the VACV inducibly expressing the A6L gene caused weight loss and mortality equivalent to wild-type VACV in the presence of tetracyclines. In the absence of tetracyclines, mice were protected from weight loss and mortality, and viral replication was not detected. These findings indicate that replication-inducible VACVs based on the conditional expression of the A3L or A6L genes can be used for the development of safer, next-generation live VACV vectors and vaccines. The design allows for administration of replication-inducible VACV in the absence of tetracyclines (as a replication-defective vector) or in the presence of tetracyclines (as a replication-competent vector) with enhanced safety.


Assuntos
Vetores Genéticos/administração & dosagem , Tetraciclinas/farmacologia , Vírus Vaccinia/crescimento & desenvolvimento , Vaccinia/prevenção & controle , Vírion/crescimento & desenvolvimento , Replicação Viral , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vacinas Sintéticas/administração & dosagem , Vaccinia/genética , Vaccinia/virologia , Vírus Vaccinia/efeitos dos fármacos , Vírus Vaccinia/genética , Proteínas Virais/genética , Vírion/efeitos dos fármacos
7.
J Chem Inf Model ; 60(6): 3277-3286, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32315171

RESUMO

The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D structures of key viral proteins are resolved. The virus causing COVID-19 is SARS-CoV-2. Taking advantage of a recently released crystal structure of SARS-CoV-2 main protease in complex with a covalently bonded inhibitor, N3 (Liu et al., 10.2210/pdb6LU7/pdb), I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an end point method called MM-PBSA-WSAS (molecular mechanics/Poisson-Boltzmann surface area/weighted solvent-accessible surface area; Wang, Chem. Rev. 2019, 119, 9478; Wang, Curr. Comput.-Aided Drug Des. 2006, 2, 287; Wang; ; Hou J. Chem. Inf. Model., 2012, 52, 1199). Several promising known drugs stand out as potential inhibitors of SARS-CoV-2 main protease, including carfilzomib, eravacycline, valrubicin, lopinavir, and elbasvir. Carfilzomib, an approved anticancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hot spot residue, His41, is a conserved residue across many viruses including SARS-CoV, SARS-CoV-2, MERS-CoV, and hepatitis C virus (HCV). The findings of this study can facilitate rational drug design targeting the SARS-CoV-2 main protease.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Betacoronavirus/química , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos/economia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Pandemias , Pneumonia Viral/virologia , Inibidores de Proteases/química , Tetraciclinas/química , Tetraciclinas/farmacologia , Termodinâmica , Fatores de Tempo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
8.
Sci Rep ; 10(1): 3937, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127598

RESUMO

For a One-Health investigation of antimicrobial resistance (AMR) in Enterococcus spp., isolates from humans and beef cattle along with abattoirs, manured fields, natural streams, and wastewater from both urban and cattle feedlot sources were collected over two years. Species identification of Enterococcus revealed distinct associations across the continuum. Of the 8430 isolates collected, Enterococcus faecium and Enterococcus faecalis were the main species in urban wastewater (90%) and clinical human isolates (99%); Enterococcus hirae predominated in cattle (92%) and feedlot catch-basins (60%), whereas natural streams harbored environmental Enterococcus spp. Whole-genome sequencing of E. faecalis (n = 366 isolates) and E. faecium (n = 342 isolates), revealed source clustering of isolates, indicative of distinct adaptation to their respective environments. Phenotypic resistance to tetracyclines and macrolides encoded by tet(M) and erm(B) respectively, was prevalent among Enterococcus spp. regardless of source. For E. faecium from cattle, resistance to ß-lactams and quinolones was observed among 3% and 8% of isolates respectively, compared to 76% and 70% of human clinical isolates. Clinical vancomycin-resistant E. faecium exhibited high rates of multi-drug resistance, with resistance to all ß-lactam, macrolides, and quinolones tested. Differences in the AMR profiles among isolates reflected antimicrobial use practices in each sector of the One-Health continuum.


Assuntos
Antibacterianos/farmacologia , Enterococcus/patogenicidade , Farmacorresistência Bacteriana/genética , Enterococcus/efeitos dos fármacos , Enterococcus/genética , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/genética , Enterococcus faecalis/patogenicidade , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/genética , Enterococcus faecium/patogenicidade , Humanos , Macrolídeos/farmacologia , Filogenia , Quinolonas/farmacologia , Tetraciclinas/farmacologia , Virulência , Sequenciamento Completo do Genoma , Resistência beta-Lactâmica/genética
9.
Int J Mol Sci ; 21(5)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32164202

RESUMO

Bacteriophages have shown promise as therapeutic alternatives to antibiotics for the control of infectious bacteria, including the human pathogen Salmonella. However, the development of effective phage-based applications requires the elucidation of key interactions between phages and target hosts, particularly since host resistance to phage is inevitable. Little is known about the alteration of host phenotypes following the development of resistance to phage. The aim of this study is to evaluate the antibiotic susceptibility and virulence of a Salmonella isolate following the development of resistance to bacteriophage SI1. We observed enhanced susceptibility to tetracycline and decreased invasion capacity in a differentiated Caco-2 intestinal cell line. Whole genome sequence analysis revealed an array of mutations, most notably, truncations in vgrG1_2, a core gene involved in Type VI secretion and mutations in the lipopolysaccharide, thereby indicating the plausible attachment site of phage SI1. These findings shed light on understanding the underlying mechanism for phage immunity within the host. Importantly, we reveal an associated genetic cost to the bacterial host with developing resistance to phages. Taken together, these results will aid in advancing strategies to delay or eliminate the development of host resistance when designing informed phage-based antimicrobials.


Assuntos
Proteínas de Bactérias/genética , Bacteriófagos/fisiologia , Intestinos/citologia , Salmonella enterica/patogenicidade , Tetraciclinas/farmacologia , Bacteriófagos/genética , Células CACO-2 , Diferenciação Celular , Aptidão Genética , Humanos , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Lipopolissacarídeos/genética , Testes de Sensibilidade Microbiana , Mutação , Salmonella enterica/genética , Salmonella enterica/virologia , Ligação Viral , Sequenciamento Completo do Genoma
10.
Environ Pollut ; 261: 114204, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32097793

RESUMO

Antibiotic and heavy metal pollution of aquatic environments are issues of serious concern, and the macrophyte Myriophyllum aquaticum may provide a viable solution for the removal of these contaminants. However, the toxic effects of coexisting tetracyclines (TCs) and Cu(II) on this plant species are currently unclear. In the present study, we constructed wetland microcosms planted with M. aquaticum and spiked these with three TCs (tetracycline, oxytetracycline, and chlortetracycline) and Cu(II) at concentrations ranging from 100 to 10,000 µg/L to investigate how Cu(II) influences the growth and tolerance responses of plants to TCs. After 12 weeks, we found that TCs had accumulated in the plants, and that plant growth and characteristics were significantly affected by the levels of both TCs and Cu(II). While low Cu(II) levels had a synergistic effect on the accumulation of TCs, high levels were observed to reduce accumulation. However, low levels of TCs and Cu(II) had a hormesis effect on plant growth, with plant biomass and leaf chlorophyll content decreasing and the malondialdehyde content and activities of antioxidant enzymes gradually increasing with an increase in TC dosage. The coexistence of low levels of Cu(II) was, however, found to alleviate these adverse effects. Principal component analysis revealed a close relationship among plant biomass, chlorophyll content, malondialdehyde content, and antioxidant enzyme activities. Considering that the Cu/TC ratio was shown to markedly affect M. aquaticum growth, the respective proportions of these pollutants should be taken into consideration in the future design of constructed wetlands.


Assuntos
Cobre , Magnoliopsida , Tetraciclinas , Áreas Alagadas , Antibacterianos/farmacologia , Cobre/farmacologia , Magnoliopsida/efeitos dos fármacos , Magnoliopsida/crescimento & desenvolvimento , Tetraciclinas/farmacologia , Poluentes Químicos da Água/farmacologia
11.
Eur J Med Chem ; 188: 112005, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31911294

RESUMO

To address the global challenge of emerging antimicrobial resistance, the hitherto most successful strategy to new antibiotics has been the optimization of validated natural products; most of these efforts rely on semisynthesis. Herein, we report the semisynthetic modification of amidochelocardin, an atypical tetracycline obtained via genetic engineering of the chelocardin producer strain. We report modifications at C4, C7, C10 and C11 by the application of methylation, acylation, electrophilic substitution, and oxidative C-C coupling reactions. The antibacterial activity of the reaction products was tested against a panel of Gram-positive and Gram-negative pathogens. The emerging structure-activity relationships (SARs) revealed that positions C7 and C10 are favorable anchor points for the semisynthesis of optimized derivatives. The observed SAR was different from that known for tetracyclines, which underlines the pronounced differences between the two compound classes.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Tetraciclinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tetraciclinas/síntese química , Tetraciclinas/química
12.
Drugs ; 80(3): 285-313, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31970713

RESUMO

Omadacycline is a novel aminomethylcycline antibiotic developed as a once-daily, intravenous and oral treatment for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). Omadacycline, a derivative of minocycline, has a chemical structure similar to tigecycline with an alkylaminomethyl group replacing the glycylamido group at the C-9 position of the D-ring of the tetracycline core. Similar to other tetracyclines, omadacycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Omadacycline possesses broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria. Omadacycline remains active against bacterial isolates possessing common tetracycline resistance mechanisms such as efflux pumps (e.g., TetK) and ribosomal protection proteins (e.g., TetM) as well as in the presence of resistance mechanisms to other antibiotic classes. The pharmacokinetics of omadacycline are best described by a linear, three-compartment model following a zero-order intravenous infusion or first-order oral administration with transit compartments to account for delayed absorption. Omadacycline has a volume of distribution (Vd) ranging from 190 to 204 L, a terminal elimination half-life (t½) of 13.5-17.1 h, total clearance (CLT) of 8.8-10.6 L/h, and protein binding of 21.3% in healthy subjects. Oral bioavailability of omadacycline is estimated to be 34.5%. A single oral dose of 300 mg (bioequivalent to 100 mg IV) of omadacycline administered to fasted subjects achieved a maximum plasma concentration (Cmax) of 0.5-0.6 mg/L and an area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 9.6-11.9 mg h/L. The free plasma area under concentration-time curve divided by the minimum inhibitory concentration (i.e., fAUC24h/MIC), has been established as the pharmacodynamic parameter predictive of omadacycline antibacterial efficacy. Several animal models including neutropenic murine lung infection, thigh infection, and intraperitoneal challenge model have documented the in vivo antibacterial efficacy of omadacycline. A phase II clinical trial on complicated skin and skin structure infection (cSSSI) and three phase III clinical trials on ABSSSI and CABP demonstrated the safety and efficacy of omadacycline. The phase III trials, OASIS-1 (ABSSSI), OASIS-2 (ABSSSI), and OPTIC (CABP), established non-inferiority of omadacycline to linezolid (OASIS-1, OASIS-2) and moxifloxacin (OPTIC), respectively. Omadacycline is currently approved by the FDA for use in treatment of ABSSSI and CABP. Phase II clinical trials involving patients with acute cystitis and acute pyelonephritis are in progress. Mild, transient gastrointestinal events are the predominant adverse effects associated with use of omadacycline. Based on clinical trial data to date, the adverse effect profile of omadacycline is similar to studied comparators, linezolid and moxifloxacin. Unlike tigecycline and eravacycline, omadacycline has an oral formulation that allows for step-down therapy from the intravenous formulation, potentially facilitating earlier hospital discharge, outpatient therapy, and cost savings. Omadacycline has a potential role as part of an antimicrobial stewardship program in the treatment of patients with infections caused by antibiotic-resistant and multidrug-resistant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA)] and Gram-negative pathogens.


Assuntos
Antibacterianos/farmacologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Dermatopatias Bacterianas/tratamento farmacológico , Tetraciclinas/administração & dosagem , Tetraciclinas/farmacologia , Administração Intravenosa , Administração Oral , Antibacterianos/administração & dosagem , Humanos
13.
In Vivo ; 34(1): 81-94, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31882466

RESUMO

BACKGROUND/AIM: Microbial tetracycline (TC) pastes have been employed to treat oral bacterial infection. In the present study, we investigated the kinetic radical-scavenging and pro-/anti-inflammatory activity of TC with or without visible light irradiation (VLI). MATERIALS AND METHODS: The radical-scavenging activity of TC and minocycline (MC) was determined by differential scanning calorimetry (DSC). The stoichiometric factor (n) and the rate constant of inhibition and propagation (kinh/kp) were determined. The levels of cyclooxygenase-2 (Cox2), tumor necrosis factor-α (Tnfα) or nitric oxide synthase 2 (Nos2) mRNA in RAW264.7 cells stimulated with lipopolysaccharide (LPS) were investigated using real-time reverse transcriptase-polymerase chain reaction. RESULTS: The n and kinh/kp values for 1 mM TC in 2,2'-azobisisobutyronitrile and benzoyl peroxide systems were 0.1-0.2 and 119-250, respectively, whereas the corresponding values for quercetin (QU) and resveratrol (RE) were 2-4 and 7-15, respectively. In RAW264.7 cells stimulated with LPS, Cox2 and Tnfα mRNA were over-expressed in the presence of TC. MC down-regulated only the expression of Cox2 by about 50% in LPS-stimulated cells. The anti-inflammatory activity determined on the basis of Cox2 inhibition declined in the order QU>RE>MC>TC. Upon application of VLI, only TC down-regulated the expression of LPS-stimulated Cox2 and Tnfα mRNA. After exposure to VLI, TC, but not MC, markedly up-regulated hemoxygenase-1 (Ho-1) expression. CONCLUSION: TC is a chain-breaking antioxidant with a large kinh Upon activation by VLI, TC may undergo degradation and its degradation products affect pleiotropic mediators such as Cox2, Tnfα and Ho-1. TC may be useful as a local photodynamic therapy for periodontal diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Fenóis/farmacologia , Tetraciclinas/farmacologia , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Antioxidantes/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Regulação para Baixo/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Doenças Periodontais/induzido quimicamente , Doenças Periodontais/tratamento farmacológico , Doenças Periodontais/metabolismo , Quercetina/farmacologia , Células RAW 264.7 , RNA Mensageiro/metabolismo , Resveratrol/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-31843997

RESUMO

Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, including those caused by resistant Gram-positive pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a recent global collection of frequently encountered clinical isolates of Gram-positive bacteria. The CLSI broth microdilution method was used to determine in vitro MIC data for isolates of Enterococcus spp. (n = 2,807), Staphylococcus spp. (n = 4,331), and Streptococcus spp. (n = 3,373) isolated primarily from respiratory, intra-abdominal, urinary, and skin specimens by clinical laboratories in 37 countries on three continents from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. There were no substantive differences (a >1-doubling-dilution increase or decrease) in eravacycline MIC90 values for different species/organism groups over time or by region. Eravacycline showed MIC50 and MIC90 results of 0.06 and 0.12 µg/ml, respectively, when tested against Staphylococcus aureus, regardless of methicillin susceptibility. The MIC90 values of eravacycline for Staphylococcus epidermidis and Staphylococcus haemolyticus were equal (0.5 µg/ml). The eravacycline MIC90s for Enterococcus faecalis and Enterococcus faecium were 0.06 µg/ml and were within 1 doubling dilution regardless of the vancomycin susceptibility profile. Eravacycline exhibited MIC90 results of ≤0.06 µg/ml when tested against Streptococcus pneumoniae and beta-hemolytic and viridans group streptococcal isolates. In this surveillance study, eravacycline demonstrated potent in vitro activity against frequently isolated clinical isolates of Gram-positive bacteria (Enterococcus, Staphylococcus, and Streptococcus spp.), including isolates collected over a 5-year period (2013 to 2017), underscoring its potential benefit in the treatment of infections caused by common Gram-positive pathogens.


Assuntos
Bactérias Gram-Positivas/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Tetraciclinas/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Vancomicina/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31843999

RESUMO

Eravacycline is a novel, fully synthetic fluorocycline antibiotic developed for the treatment of serious infections, including those caused by multidrug-resistant (MDR) pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a global collection of frequently encountered clinical isolates of Gram-negative bacilli. The CLSI broth microdilution method was used to determine MIC data for isolates of Enterobacterales (n = 13,983), Acinetobacter baumannii (n = 2,097), Pseudomonas aeruginosa (n = 1,647), and Stenotrophomonas maltophilia (n = 1,210) isolated primarily from respiratory, intra-abdominal, and urinary specimens by clinical laboratories in 36 countries from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. Multidrug-resistant (MDR) isolates were defined by resistance to agents from ≥3 different antimicrobial classes. The MIC90s ranged from 0.25 to 1 µg/ml for Enterobacteriaceae and were 1 µg/ml for A. baumannii and 2 µg/ml for S. maltophilia, Proteus mirabilis, and Serratia marcescens Eravacycline's potency was up to 4-fold greater than that of tigecycline against genera/species of Enterobacterales, A. baumannii, and S. maltophilia The MIC90s for five of six individual genera/species of Enterobacterales and A. baumannii were within 2-fold of the MIC90s for their respective subsets of MDR isolates, while the MDR subpopulation of Klebsiella spp. demonstrated 4-fold higher MIC90s. Eravacycline demonstrated potent in vitro activity against the majority of clinical isolates of Gram-negative bacilli, including MDR isolates, collected over a 5-year period. This study further underscores the potential benefit of eravacycline in the treatment of infections caused by MDR Gram-negative pathogens.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Tetraciclinas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Tigeciclina/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-31844016

RESUMO

Antimicrobial-resistant Cutibacterium acnes strains have emerged and disseminated throughout the world. The 23S rRNA mutation and erm(X) gene are known as the major resistance determinants of macrolides and clindamycin in C. acnes We isolated eight high-level macrolide-clindamycin-resistant C. acnes strains with no known resistance determinants, such as 23S rRNA mutation and erm(X), from different acne patients in 2008 between 2013 and 2015. The aim of this study was to identify the novel mechanisms of resistance in C. acnes Whole-genome sequencing revealed the existence of a plasmid DNA, denoted pTZC1 (length, 31,440 bp), carrying the novel macrolide-clindamycin resistance gene erm(50) and tetracycline resistance gene tet(W). pTZC1 was detected in all C. acnes isolates (eight strains) exhibiting high-level macrolide-clindamycin resistance, with no known resistance determinants (MIC of clarithromycin, ≥256 µg/ml; clindamycin, ≥256 µg/ml). Transconjugation experiments demonstrated that the pTZC1 was horizontally transferred among C. acnes strains and conferred resistance to macrolides, clindamycin, and tetracyclines. Our data showed, for the first time, the existence of a transferable multidrug-resistant plasmid in C. acnes Increased prevalence of this plasmid will be a great threat to antimicrobial therapy for acne vulgaris.


Assuntos
Clindamicina/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Genoma Bacteriano , Macrolídeos/farmacologia , Plasmídeos/química , Propionibacteriaceae/genética , Acne Vulgar/microbiologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Conjugação Genética , Expressão Gênica , Transferência Genética Horizontal , Humanos , Testes de Sensibilidade Microbiana , Filogenia , Plasmídeos/metabolismo , Propionibacteriaceae/classificação , Propionibacteriaceae/efeitos dos fármacos , Propionibacteriaceae/isolamento & purificação , RNA Ribossômico 23S/genética , RNA Ribossômico 23S/metabolismo , Resistência a Tetraciclina/genética , Tetraciclinas/farmacologia , Sequenciamento Completo do Genoma
17.
Artigo em Inglês | MEDLINE | ID: mdl-31871086

RESUMO

This study aimed to evaluate the in vitro antimicrobial activity, heteroresistance emergence, and resistance mechanism of omadacycline (OMC) in clinical Enterococcus faecalis isolates from China. A total of 276 isolates were collected retrospectively in China from 2011 to 2015. The MICs of OMC, doxycycline (DOX), and minocycline (MIN) against E. faecalis were determined by broth microdilution. Tetracycline (TET)-specific resistance genes and multilocus sequence typing (MLST) of the isolates were investigated using PCR. The detection frequency of OMC heteroresistance in E. faecalis was evaluated with population analysis profiling (PAP). The mechanism of OMC heteroresistance and resistance in E. faecalis was examined by amplifying 30S ribosomal subunit genes, RNA sequencing (RNA-Seq), and in vitro recombination experiments. The OMC MICs of clinical E. faecalis isolates ranged from ≤0.06 to 1.0 mg/liter, and 42% of the E. faecalis isolates with an OMC MIC of 1.0 mg/liter were found to be sequence type 16 (ST16). Six OMC-heteroresistant isolates with MIC values of ≤0.5 mg/liter were detected among 238 E. faecalis isolates. The resistant subpopulations of heteroresistant isolates showed OMC MICs in the range of 2 to 4 mg/liter and were found without 30S ribosomal subunit gene mutations. Moreover, RNA sequencing and in vitro recombination experiments demonstrated that overexpression of a bone morphogenetic protein (BMP) family ATP-binding cassette (ABC) transporter substrate-binding protein, OG1RF_RS00630, facilitated OMC heteroresistance in E. faecalis In conclusion, OMC exhibited better activity against clinical E. faecalis isolates from China than that of DOX or MIN, and overexpression of OG1RF_RS00630 in E. faecalis facilitated the development of OMC heteroresistance.


Assuntos
Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/genética , Tetraciclinas/farmacologia , China , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Mutação/genética , Subunidades Ribossômicas Menores de Bactérias/genética , Análise de Sequência de RNA
18.
Mater Sci Eng C Mater Biol Appl ; 105: 110132, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546396

RESUMO

In this work, nitrogen and sulfur dual-doped carbon quantum dots (N,S-CDs) from naturally renewable biomaterial fungus fibers were prepared by a biosynthesis and hydrothermal method. The N,S-CDs displayed good water solubility, excellent stability, high quantum yield (QY = 28.11%) as well as remarkable features for fluorescence quenching-based detection and cellular imaging of cancer cells. It was worth mentioning that the heteroatoms doped carbon quantum dots made from the fungus fibers had a satisfactory QY and could be used as a selective, efficient, and sensitive fluorescent probe to determine tetracyclines by the synergistic effects of static quenching and internal filtration effect. The probe demonstrated a wide linear range and low detection limit. For tetracycline, the linear range was 0.5 µM to 47.6 µM, and the corresponding detection limit was 15.6 nM. Significantly, the test papers prepared by using N,S-CDs could detect tetracyclines in aquiculture wastewater rapidly. The produced N,S-CDs did not affect the cell viability and showed great promises for cellular imaging.


Assuntos
Carbono/química , Fungos/química , Imageamento Tridimensional , Neoplasias/diagnóstico por imagem , Nitrogênio/química , Pontos Quânticos/química , Enxofre/química , Tetraciclinas/análise , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias/patologia , Tamanho da Partícula , Pontos Quânticos/ultraestrutura , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Tetraciclinas/farmacologia , Águas Residuárias/química
19.
Emerg Microbes Infect ; 8(1): 1219-1222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31429665

RESUMO

Plasmid-mediated antimicrobial resistance has emerged as one of the principal global issues, posing significant threats to public health. Herein, we reported a mobile tigecycline resistance mechanism Tet(X4) on both plasmid and chromosome in Escherichia coli strains from migratory birds in China. Besides tigecycline, these tet(X4)-positive strains also exhibited elevated MICs to the FDA newly approved tetracycline antibiotics, eravacycline (4 µg/ml) and omadacycline (8 µg/ml). Worrisomely, the tet(X4)-carrying plasmids and chromosome also shared high homology with the plasmids from human. Taken together, Tet(X4) represents another emerging antimicrobial threat and collective efforts from different sectors are needed to control its further spread.


Assuntos
Antibacterianos/farmacologia , Aves/microbiologia , Farmacorresistência Bacteriana , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Sequências Repetitivas Dispersas , Tigeciclina/farmacologia , Animais , China , Cromossomos Bacterianos , Escherichia coli/genética , Genes Bacterianos , Testes de Sensibilidade Microbiana , Plasmídeos , Homologia de Sequência , Tetraciclinas/farmacologia
20.
Int J Antimicrob Agents ; 54(5): 531-537, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437486

RESUMO

There are substantial limitations in understanding of the distribution of antimicrobial resistance (AMR) in humans and livestock in developing countries. This papers present the results of an epidemiological study examining patterns of AMR in Escherichia coli isolates circulating in sympatric human (n = 321) and livestock (n = 633) samples from 99 households across Nairobi, Kenya. E. coli isolates were tested for susceptibility to 13 antimicrobial drugs representing nine antibiotic classes. High rates of AMR were detected, with 47.6% and 21.1% of isolates displaying resistance to three or more and five or more antibiotic classes, respectively. Human isolates showed higher levels of resistance to sulfonamides, trimethoprim, aminoglycosides and penicillins compared with livestock (P<0.01), while poultry isolates were more resistant to tetracyclines (P = 0.01) compared with humans. The most common co-resistant phenotype observed was to tetracyclines, streptomycin and trimethoprim (30.5%). At the household level, AMR carriage in humans was associated with human density (P<0.01) and the presence of livestock manure (P = 0.03), but keeping livestock had no influence on human AMR carriage (P>0.05). These findings revealed a high prevalence of AMR E. coli circulating in healthy humans and livestock in Nairobi, with no evidence to suggest that keeping livestock, when treated as a single risk factor, contributed significantly to the burden of AMR in humans, although the presence of livestock waste was significant. These results provide an understanding of the broader epidemiology of AMR in complex and interconnected urban environments.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/fisiologia , Infecções por Escherichia coli/epidemiologia , Escherichia coli/efeitos dos fármacos , Gado/microbiologia , Aves Domésticas/microbiologia , Aminoglicosídeos/farmacologia , Animais , Estudos Transversais , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Quênia/epidemiologia , Testes de Sensibilidade Microbiana , Penicilinas/farmacologia , Sulfonamidas/farmacologia , Tetraciclinas/farmacologia , Trimetoprima/farmacologia
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