RESUMO
The quantitative structure-activity relationship (QSAR) is one of the most popular methods for the virtual screening of new drug leads and optimization. Herein, we collected a dataset of 955 MIC values of pleuromutilin derivatives to construct a 2D-QSAR model with an accuracy of 80% and a 3D-QSAR model with a non-cross-validated correlation coefficient (r2) of 0.9836 and a cross-validated correlation coefficient (q2) of 0.7986. Based on the obtained QSAR models, we designed and synthesized pleuromutilin compounds 1 and 2 with thiol-functionalized side chains. Compound 1 displayed the highest antimicrobial activity against both Staphylococcus aureus ATCC 29213 (S. aureus) and Methicillin-resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentrations (MICs) < 0.0625 µg/mL. These experimental results confirmed that the 2D and 3D-QSAR models displayed a high accuracy of the prediction function for the discovery of lead compounds from pleuromutilin derivatives.
Assuntos
Diterpenos , Staphylococcus aureus Resistente à Meticilina , Compostos Policíclicos , Pleuromutilinas , Antibacterianos/química , Relação Quantitativa Estrutura-Atividade , Staphylococcus aureus , Diterpenos/química , Compostos Policíclicos/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Simulação de Acoplamento MolecularRESUMO
Antibiotic-resistant bacteria pose a major global public health concern, owing to the lack of effective antibacterial drugs. Consequently, the discovery and development of innovative antibacterial drug classes with unique mechanisms of action are urgently needed. In this study, we designed, synthesised, and tested a series of novel pleuromutilin derivatives with piperazine linker substituted by amino acids moieties to determine their antibacterial properties. Most synthesized compounds exhibited potent activities against Staphylococcus aureus (S. aureus), methicillin-resistant S. aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis. Compound 6l, the most potent antibacterial agent created in this study, displayed a rapid bactericidal activity against MRSA, Klebsiella pneumoniae and S. aureus cfr N12. Moreover, pharmacokinetics study of compound 6l exhibited good PK performance with a low in vivo clearance (CL = 1965 mL/h/kg) and a suitable half-life (T1/2 = 11.614 ± 5.123 h). Molecular docking experiments revealed the binding model of compound 6l to the unmethylated A2503 of peptidyl transferase centre of 23S rRNA. Interaction pattern of 6l with cfr-mediated ribosomes revealed by molecular dynamics. Moreover in vivo mouse systemic infection experiments with compound 6l revealed its effectiveness against MRSA and S. aureus cfr N12 with the ED50 of 11.08 mg/kg and 14.63 mg/kg body weight, respectively.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Camundongos , Animais , Staphylococcus aureus , Simulação de Acoplamento Molecular , Piperazina/farmacologia , Testes de Sensibilidade Microbiana , Resistência Microbiana a Medicamentos , Antibacterianos/química , Staphylococcus epidermidis , Infecções Estafilocócicas/tratamento farmacológico , PleuromutilinasRESUMO
Composting is a common practice used for treating animal manures before they are used as organic fertilizers for crop production. Whether composting can effectively reduce microbial pathogens and antibiotic resistance genes remain poorly understood. In this study, we compared 3 different dairy manure composting methods-anaerobic fermentation (AF), static compost (SC), and organic fertilizer production (OFP)-for their effects on antibiotic-resistant bacteria, antibiotic resistance genes, and microbial community diversity in the treated manures. The 3 composting methods produced variable and distinct effects on antibiotic-resistant bacteria, zoonotic bacteria, and resistance genes, some of which were decreased and others of which showed no significant changes during composting. Particularly, SC and OFP reduced chloramphenicol resistance gene fexA and opportunistic pathogen Vibrio fluvialis, whereas AF significantly reduced tetracycline resistance gene tetB and opportunistic pathogens Enterococcus faecium and Escherichia fergusonii. The compositions of microbial communities varied significantly during the composting processes, and there were significant differences between the 3 composting methods. In all 3 composts, the dominant phyla were Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria. Interestingly, Firmicutes, Proteobacteria, and Bacteroidetes remained stable in the entire AF process, whereas they were dominated at the beginning, decreased at the early stage of composting, and rebounded at the later stage during SC and OFP. In general, SC and OFP produced a more profound effect than AF on microbial community diversities, pathogens, and dominant species. Additionally, Enterococcus aquimarinus was isolated from AF for the first time. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States function prediction analysis indicated that the genes related to membrane transport and amino acid metabolism were abundant in the 3 composts. The metabolism of amino acids, lipids, and carbohydrates increased as composting progressed. The biosynthesis of antibiotics was enhanced after fermentation in the 3 composting methods, and the increase in the SC was the most obvious. These results reveal dynamic changes in antibiotic-resistant bacteria, antibiotic resistance genes, microbial community composition, and function succession in different dairy manure composts and provide useful information for further optimization of composting practices.
Assuntos
Compostagem , Bovinos , Animais , Esterco/microbiologia , Antibacterianos/farmacologia , Filogenia , Microbiologia do Solo , Resistência Microbiana a Medicamentos/genética , Bactérias , Genes Bacterianos , SoloRESUMO
To investigate the effect of polymer blends on the in vitro release/degradation and pharmacokinetics of moxidectin-loaded PLGA microspheres (MOX-MS), four formulations (F1, F2, F3 and F4) were prepared using the O/W emulsion solvent evaporation method by blending high (75/25, 75 kDa) and low (50/50, 23 kDa) molecular weight PLGA with different ratios. The addition of low-molecular-weight PLGA did not change the release mechanism of microspheres, but sped up the drug release of microspheres and drastically shortened the lag phase. The in vitro degradation results show that the release of microspheres consisted of a combination of pore diffusion and erosion, and especially autocatalysis played an important role in this process. Furthermore, an accelerated release method was also developed to reduce the period for drug release testing within one month. The pharmacokinetic results demonstrated that MOX-MS could be released for at least 60 days with only a slight blood drug concentration fluctuation. In particular, F3 displayed the highest AUC and plasma concentration (AUC0-t = 596.53 ng/mL·d, Cave (day 30-day 60) = 8.84 ng/mL), making it the optimal formulation. Overall, these results indicate that using polymer blends could easily adjust hydrophobic drug release from microspheres and notably reduce the lag phase of microspheres.
Assuntos
Ácido Láctico , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ácido Láctico/química , Ácido Poliglicólico/química , Microesferas , Tamanho da PartículaRESUMO
The redox system is closely related to changes in cellular metabolism. Regulating immune cell metabolism and preventing abnormal activation by adding antioxidants may become an effective treatment for oxidative stress and inflammation-related diseases. Quercetin is a naturally sourced flavonoid with anti-inflammatory and antioxidant activities. However, whether quercetin can inhibit LPS-induced oxidative stress in inflammatory macrophages by affecting immunometabolism has been rarely reported. Therefore, the present study combined cell biology and molecular biology methods to investigate the antioxidant effect and mechanism of quercetin in LPS-induced inflammatory macrophages at the RNA and protein levels. Firstly, quercetin was found to attenuate the effect of LPS on macrophage proliferation and reduce LPS-induced cell proliferation and pseudopodia formation by inhibiting cell differentiation, as measured by cell activity and proliferation. Subsequently, through the detection of intracellular reactive oxygen species (ROS) levels, mRNA expression of pro-inflammatory factors and antioxidant enzyme activity, it was found that quercetin can improve the antioxidant enzyme activity of inflammatory macrophages and inhibit their ROS production and overexpression of inflammatory factors. In addition, the results of mitochondrial morphology and mitochondrial function assays showed that quercetin could upregulate the mitochondrial membrane potential, ATP production and ATP synthase content decrease induced by LPS, and reverse the mitochondrial morphology damage to a certain extent. Finally, Western blotting analysis demonstrated that quercetin significantly upregulated the protein expressions of SIRT1 and PGC-1α, that were inhibited by LPS. And the inhibitory effects of quercetin on LPS-induced ROS production in macrophages and the protective effects on mitochondrial morphology and membrane potential were significantly decreased by the addition of SIRT1 inhibitors. These results suggested that quercetin reprograms the mitochondria metabolism of macrophages through the SIRT1/PGC-1α signaling pathway, thereby exerting its effect of alleviating LPS-induced oxidative stress damage.
Assuntos
Antioxidantes , Quercetina , Quercetina/farmacologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Lipopolissacarídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Estresse Oxidativo , Macrófagos/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismoRESUMO
BACKGROUND: This study investigated the effects of terpinen-4-ol on methicillin-resistant Staphylococcus aureus (MRSA) and its biofilm, and the possible mechanisms governing this effect. RESULTS: We observed that terpinen-4-ol has good antibacterial activity and inhibits the formation of MRSA biofilm. The MIC and MBC values for terpinen-4-ol against S. aureus were 0.08% ~ 0.32%. And terpinen-4-ol at 0.32% could kill all bacteria and clear all biofilms. Untargeted metabolomic and transcriptomic analyses showed that terpinen-4-ol strongly inhibited DNA and RNA biosynthesis in MRSA at 2 h after treatment by affecting genes and metabolites related to purine and pyrimidine metabolic pathways. Some differential genes which play important roles in DNA synthesis and the production of eDNA from biofilm exposed to terpinen-4-ol was also significantly decreased compared with that of the control. CONCLUSIONS: Terpinen-4-ol has good antibacterial activity and significantly inhibits the formation of MRSA biofilm by inhibiting purine and pyrimidine metabolism.
Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Terpenos/farmacologia , Biofilmes/efeitos dos fármacos , Metabolômica , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , TranscriptomaRESUMO
A new pleuromutilin derivative, 14-O-[(4,6-Diaminopyrimidine-2-yl) thioacetyl] mutilin (DPTM), has been synthesized and proven to be a potent agent against Gram-positive pathogens, especially for Staphylococcus aureus (S. aureus). However, its pharmacological activities against α-hemolysin (Hla), a major virulence factor produced by S. aureus, and inflammations related to S. aureus are still unknown. In the present study, we investigated the DPTM inhibition activities against methicillin-resistant S. aureus (MRSA) Hla and protective efficacy of Raw264.7 cells from injury induced by MRSA. The results showed that DPTM with sub-inhibitory concentrations significantly inhibited Hla on the hemolysis of rabbit erythrocytes and down-regulated the gene expressions of Hla and agrA with a dose-dependent fashion. In Raw264.7 cells infected with MRSA, DPTM efficiently attenuated the productions of lactate dehydrogenase (LDH), nitric oxide (NO) and pro-inflammatory cytokines, as well as the express levels of nuclear factor-kappaB (NF-κB), nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, DPTM inhibited the translocation of p-65 to nucleus in RAW264.7 cells infected by MRSA.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Animais , Antibacterianos/farmacologia , Proteínas Hemolisinas , Cetonas , Resistência a Meticilina , Compostos Policíclicos , Coelhos , Staphylococcus aureusRESUMO
Staphylococcus aureus (S. aureus) is a major human pathogen that requires new antibiotics with unique mechanism. A new pleuromutilin derivative, 14-O-[(4,6-Diamino-pyrimidine-2-yl) thioacetyl] mutilin (DPTM), has been synthesized and proved as a potent antibacterial agent using in vitro and in vivo assays. In the present study, DPTM was further in vitro evaluated against methicillin-resistant Staphylococcus aureus (MRSA) isolated from dairy farms and outperformed tiamulin fumarate, a pleuromutilin drug used for veterinary. Moreover, a murine skin wound model caused by MRSA infection was established, and the healing effect of DPTM was investigated. The results showed that DPTM could promote the healing of MRSA skin infection, reduce the bacterial burden of infected skin MRSA and decrease the secretion of IL-6 and TNF-α inflammatory cytokines in plasma. These results provided the basis for further in-depth drug targeted studies of DPTM as a novel antibacterial agent.
Assuntos
Antibacterianos/farmacologia , Cetonas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Compostos Policíclicos/química , Animais , Bovinos , Citocinas/metabolismo , Diterpenos/farmacologia , Desenho de Fármacos , Técnicas In Vitro , Inflamação , Interleucina-6/metabolismo , Leucócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Leite/microbiologia , Simulação de Acoplamento Molecular , Pele/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese , Cicatrização , PleuromutilinasRESUMO
This study assessed the antimicrobial activity of 14-O-[(4,6-Diaminopyrimidine-2-yl) thioacetyl] mutilin (DPTM), a novel pleuromutilin candidate with a substituted pyrimidine moiety, against Pasteurella multocida. Minimum Inhibitory Concentration (MIC), Oxford Cup assay, and time-kill experiments were used to measure the activity of DPTM against P. multocida serotype A in vitro. We observed that DPTM was potent against Pasteurella multocida serotype A with the MIC value of 0.781⯵g/mL. The mean inhibition-zone diameters of DPTM (50, 25, and 12.5⯵g/mL) were 29.4, 24.2 and 20.1â¯mm, respectively. Time-kill experiments showed that the drug caused a rapid decline in the number of bacteria compared with the initial inoculum at 4â¯h and killed 94.6% of the bacteria during 24â¯h. Furthermore, DPTM activity was also assessed in a lung infection model challenged with 4.0â¯×â¯109â¯CFU/mL P. multocida serotype A. The results showed that DPTM significantly reduced mortality rate and bacterial load, and alleviated the pathological changes of lung. The antibacterial effect of DPTM found in this study suggested that it was useful in the prevention or control of pneumonia caused by P. multocida.
Assuntos
Antibacterianos/farmacologia , Pasteurella multocida/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Diterpenos/administração & dosagem , Diterpenos/química , Diterpenos/farmacologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Infecções por Pasteurella/tratamento farmacológico , Infecções por Pasteurella/microbiologia , Infecções por Pasteurella/patologia , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Compostos Policíclicos , Resultado do Tratamento , PleuromutilinasRESUMO
14-O-[(4,6-Diaminopyrimidine-2-yl)thioacetyl] mutilin (DPTM), a novel pleuromutilin candidate with a substituted pyrimidine moiety, has been confirmed to possess excellent antibacterial activity against Gram-positive bacteria. To illustrate the pharmacokinetic profile after intravenous (i.v.), intramuscular (i.m.) and oral (p.o.) administrations with DPTM, as well as tissue distribution and excretion via urine and feces in vivo, a specific, sensitive and robust HPLC-MS/MS method was first developed to determine DPTM in rat plasma, various tissues, urine and feces. The plasma, tissues, urine and feces samples were treated by protein precipitation with acetonitrile using tiamulin fumarate as an internal standard (IS). This method which was achieved on an HPLC system detector equipped with an ESI interface, was sensitive with 5 ng/mL as the lower limit of detection and exhibited good linearity (R² > 0.9900) in the range of 5â»4000 ng/mL for plasma, various tissues, urine and feces, as well as intra-day precision, inter-day precision and accuracy. The matrix effects ranged from 94.2 to 109.7% with RSD ≤ 9.4% and the mean extraction recoveries ranged from 95.4 to 109.5% in plasma, tissue homogenates, urine and feces (RSD ≤ 9.9). After i.v., i.m. and p.o. administrations, DPTM was rapidly absorbed and metabolized in rats with the half-life (t1/2) of 1.70â»1.86, 3.23â»3.49 and 4.38â»4.70 for 10, 25 and 75 mg/kg doses, respectively. The tissue distribution showed that DPTM was diffused into all the tested tissues, especially into the intestine and lung. Excretion via urine and feces studies demonstrated that DPTM was mainly excreted by feces after administration.
Assuntos
Líquidos Corporais/química , Fezes/química , Cetonas/administração & dosagem , Cetonas/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Antibacterianos , Cromatografia Líquida de Alta Pressão , Meia-Vida , Injeções Intramusculares , Intestinos/química , Cetonas/urina , Limite de Detecção , Pulmão/química , Masculino , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/farmacocinética , Compostos Policíclicos/urina , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
A new pleuromutilin derivative, 14-O-[(4-Amino-6-hydroxy-pyrimidine-2-yl)thioacetyl] mutilin (APTM), has been synthesized and proved most potent antibacterial agent in in vitro assays, suggesting that further development of this compound may lead to a promising antibacterial drug. In this study, we further evaluated the cytotoxicity, antibacterial efficacy and the pharmacokinetic profile of APTM. In BRL 3A cells, 50% of viability was obtained when 363µg/mL of APTM was used, while retapamulin and tiamulin fumarate needed 49 and 28µg/mL, respectively, to reach this viability. Compared to tiamulin fumarate, APTM showed higher inhibition efficacy and faster bactericidal activity against S. aureus and lower 50% effective dose (ED50) in mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA). Docking experiment for APTM showed a similar binding pattern with tiamulin. Furthermore, a simple, accurate and sensitive HPLC method for the determination of APTM in rabbit plasma was developed and successfully applied to pharmacokinetic study, in which the half life (t1/2), clearance rate (Cl) and the area under the plasma concentration-time curve (AUC0â∞) were 3.37h, 0.35L/h/kg and 70.68µg·h/m, respectively.
Assuntos
Antibacterianos/farmacologia , Animais , Feminino , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , CoelhosRESUMO
Pleuromutilin derivatives 4a-h, 5a-g, and 6a-d were synthesized and characterized by IR, 1 H NMR, and 13 C NMR. All synthetic compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus (ATCC 25923), methicillin-resistant S. aureus (MRSA, ATCC 43300), Pasteurella multocida (CVCC 408), Escherichia coli (ATCC 25922), and Salmonella typhimurium (ATCC 14028). Most compounds with quaternary amine showed higher antibacterial activities against both Gram-positive and Gram-negative bacteria strains. Among the screened compounds, compound 5a bearing an N,N,N-trimethyl group at the C-14 side chain of pleuromutilin was found to be the most active agent. Furthermore, preliminary molecular docking was performed to predict the binding interaction of the compounds in the binding pocket.
Assuntos
Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pasteurella multocida/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/química , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Escherichia coli/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Pasteurella multocida/crescimento & desenvolvimento , Compostos Policíclicos , Ratos , Salmonella typhimurium/crescimento & desenvolvimento , Relação Estrutura-Atividade , PleuromutilinasRESUMO
A series of pleuromutilin derivatives were synthesized by two synthetic procedures under mild reaction conditions and characterized by Nuclear Magnetic Resonance (NMR), Infrared Spectroscopy (IR), and High Resolution Mass Spectrometer (HRMS). Most of the derivatives with heterocyclic groups at the C-14 side of pleuromutilin exhibited excellent in vitro antibacterial activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococcus (VRE) in vitro antibacterial activity. The synthesized derivatives which contained pyrimidine rings, 3a, 3b, and 3f, displayed modest antibacterial activities. Compound 3a, the most active antibacterial agent, displayed rapid bactericidal activity and affected bacterial growth in the same manner as that of tiamulin fumarate. Moreover, molecular docking studies of 3a and lefamulin provided similar information about the interactions between the compounds and 50S ribosomal subunit. The results of the study show that pyrimidine rings should be considered in the drug design of pleuromutilin derivatives.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Simulação de Acoplamento Molecular , Antibacterianos/química , Diterpenos/química , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Compostos Policíclicos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , PleuromutilinasRESUMO
A series of novel pleuromutilin derivatives with substituted benzimidazole moieties were designed and synthesized from pleuromutilin and 5-amino-2-mercaptobenzimidazole through sequential reactions. All the newly synthesized compounds were characterized by IR, NMR, and HRMS. Each of the derivatives was evaluated in vitro for their antibacterial activity against Escherichia coli (E. coli) and five Gram (+) inoculums. 14-O-((5-amino-benzimidazole-2-yl) thioacetyl) mutilin (3) was the most active compound and showed highest antibacterial activities. Furthermore, we evaluated the inhibition activities of compound 3 on short-term S. aureus and MRSA growth and cytochrome P450 (CYP). The bioassay results indicate that compound 3 could be considered potential antibacterial agents but with intermediate inhibition of CYP3A4.
Assuntos
Antibacterianos/síntese química , Benzimidazóis/síntese química , Inibidores das Enzimas do Citocromo P-450/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Diterpenos/química , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana/métodos , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Policíclicos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , PleuromutilinasRESUMO
Platensimycin and platencin were successively discovered from the strain Streptomyces platensis through systematic screening. These natural products have been defined as promising agents for fighting multidrug resistance in bacteria by targeting type II fatty acid synthesis with slightly different mechanisms. Bioactivity studies have shown that platensimycin and platencin offer great potential to inhibit many resistant bacteria with no cross-resistance or toxicity observed in vivo. This review summarizes the general information on platensimycin and platencin, including antibacterial and self-resistant mechanisms. Furthermore, the total synthesis pathways of platensimycin and platencin and their analogues from recent studies are presented.
Assuntos
Adamantano/farmacologia , Aminobenzoatos/farmacologia , Aminofenóis/farmacologia , Anilidas/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Adamantano/química , Aminobenzoatos/química , Aminofenóis/química , Anilidas/química , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Estrutura Molecular , Compostos Policíclicos/química , Streptomyces/químicaRESUMO
A new pleuromutilin derivative with excellent antibacterial activity, 14-O-[(2-amino-1,3,4-thiadiazol-5-yl) thioacetyl] mutilin (ATTM), may serve as a possible lead compound for the development of antibacterial drugs. However, in vivo efficacy and toxicity evaluations of this compound have not been performed. In this study, we evaluated the efficacy of ATTM by measuring the survival of mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA), and the 50% effective dose (ED50) was 5.74 mg/kg by the intravenous route. In an oral single-dose toxicity study, ATTM was orally administered to mice at different doses and the 50% lethal dose (LD50) was calculated to be 2304.4 mg/kg by the Bliss method. The results of the subchronic oral toxicity study in rats showed no mortality, exterior signs of toxicity, or differences in the total weight gain or relative organ weights between the treated groups and control group after administration. The hematological and serum biochemical data showed no differences between the treated and control groups, except for the levels of alkaline phosphatase (ALP), creatinine (CR) and blood glucose (GLU), which were significantly different in the high-dose group. The differences in the histopathological findings between the treated groups and the control group were not considered to be treatment-related. Our results indicated that the no observed adverse effect level (NOAEL) for ATTM was 5 mg/kg in this study.
Assuntos
Antibacterianos/administração & dosagem , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/mortalidade , Administração Intravenosa , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Diterpenos/administração & dosagem , Diterpenos/química , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Nível de Efeito Adverso não Observado , Compostos Policíclicos , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/veterinária , Testes de Toxicidade Aguda , PleuromutilinasRESUMO
Several pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant S. aureus, methicillin-resistant S. epidermidis, S. aureus, S. epidermidis, E. coli, and B. cereus were tested by the agar dilution method and Oxford cup assay. All the screened compounds displayed potent activity. Compound 6d was the most active antibacterial agent because of its lowest MIC value and largest inhibition zone. Docking experiments were performed to understand the possible mode of the interactions between the derivatives and 50S ribosomal subunit. Moreover, the absorption, distribution, metabolism, excretion and toxicity properties of the synthesized compounds were analyzed after prediction using the Advanced Chemistry Development/Percepta Platform available online.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/farmacologia , Testes de Sensibilidade Microbiana/métodos , Simulação de Acoplamento Molecular , Compostos Policíclicos , PleuromutilinasRESUMO
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have threated the public health worldwide, which emphasizes the urgent need for new drugs with novel mechanism of actions. 14-O-[(5-ethoxycarbonyl-4,6-dimethylpyrimidine-2-yl) thioacetyl] mutilin (EDT) is a pleuromutilin compound with high activity against several Gram-positive bacteria in vitro and in vivo. This study aimed to verifying the potential anti-MRSA activity and evaluating the safety of EDT. In in vitro antibacterial activity assays, EDT exhibited potent antibacterial activity against MRSA isolated from clinic (minimum inhibitory concentration = 0.0313-0.125 µg/mL), increased post-antibiotic effect (PAE) values and limited potential for the development of resistance. Docking model and green fluorescent protein (GFP) inhibition assay further elucidated the higher antibacterial activities of EDT via mechanism of action. In safety evaluation, EDT exhibited low cytotoxic effect and acute oral toxicity in mice and avoided to significantly increase the number of revertant colonies of six tested strains in the Ames study. Furthermore, EDT displayed a moderate inhibitory effect on CYP3A4 and moderate stability in mouse and human liver microsomes, providing a promising agent for the development of new antimicrobial candidate.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Humanos , Animais , Camundongos , Cetonas , Instituições de Assistência Ambulatorial , Antibacterianos/farmacologiaRESUMO
Multidrug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus, have become a major global public health concern. Therefore, developing new antibiotics that do not possess cross-resistance for the currently available antibiotics is critical. Herein, we synthesized a novel class of pleuromutilin derivatives containing substituted triazine with improved antibacterial activity. Among these derivatives, 6d, which contains 4-dimethylamino-1,3,5-triazine in the side chain of pleuromutilin, exhibited highly promising antimicrobial activity and mitigated antibiotic resistance. The high antibacterial potency of 6d was further supported by docking model analysis and green fluorescent protein inhibition assay. Additionally, cytotoxicity and acute oral toxicity evaluation and in vivo mouse systemic infection experiments revealed that 6d possessed tolerable toxicity and promising therapeutic efficacy.
Assuntos
Diterpenos , Staphylococcus aureus Resistente à Meticilina , Compostos Policíclicos , Animais , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Antibacterianos/química , Diterpenos/farmacologia , Diterpenos/química , Compostos Policíclicos/farmacologia , Triazinas/farmacologia , Subunidades Ribossômicas/metabolismo , PleuromutilinasRESUMO
A series of pyridinium cation-substituted pleuromutilin analogues were designed, synthesized and evaluated for their antibacterial activities in vitro and in vivo. Most derivatives showed potent antibacterial activities, especially e4 that displayed the highest antibacterial activity against multi-drug resistant bacteria and was subjected to time-kill kinetics, resistance studies, cytotoxicity and molecular docking assays. Molecular docking results, scanning electron microscopy and o-nitrophenyl-ß-galactopyranoside tests showed that e4 not only inhibited bacterial protein synthesis but also disrupted bacterial cell walls. Compound e4 showed an ED50 of 5.68 mg/kg against multi-drug resistant Staphylococcus aureus in infected mice model. In in vivo and in vitro toxicity tests, e4 showed low toxic effects with an LD50 of 879 mg/kg to mice. These results suggest that compound e4 may be considered as a new therapeutic candidate for bacterial infections.