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1.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201372

RESUMO

A novel pleuromutilin derivative, 22-(4-(2-(4-nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin (NPDM), was synthesized in our laboratory and proved excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, more methods were used to further study its preliminary pharmacological effect. The antibacterial efficacy and toxicity of NPDM were evaluated using tiamulin as the reference drug. The in vitro antibacterial activity study showed that NPDM is a potent bactericidal agent against MRSA that induced time-dependent growth inhibition and a concentration-dependent post-antibiotic effect (PAE). Toxicity determination showed that the cytotoxicity of NPDM was slightly higher than that of tiamulin, but the acute oral toxicity study proved that NPDM was a low-toxic compound. In an in vivo antibacterial effect study, NPDM exhibited a better therapeutic effect than tiamulin against MRSA in a mouse thigh infection model as well as a mouse systemic infection model with neutropenia. The 50% effective dose (ED50) of NPDM in a Galleria mellonella infection model was 50.53 mg/kg. The pharmacokinetic properties of NPDM were also measured, which showed that NPDM was a rapid elimination drug in mice.


Assuntos
Antibacterianos/farmacologia , Diterpenos/farmacologia , Nitrofenóis/farmacologia , Piperazina/farmacologia , Compostos Policíclicos/farmacologia , Animais , Linhagem Celular , Insetos/microbiologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana/métodos , Ratos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia
2.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203787

RESUMO

Herein, we report antibacterial and antifungal evaluation of a series of previously prepared (+)-tanikolide analogues. One analogue, (4S,6S)-4-methyltanikolide, displayed promising anti-methicillin-resistant Staphylococcus aureus activity with a MIC of 12.5 µg/mL. Based on the antimicrobial properties of the structurally related (-)-malyngolide, two further analogues (4S,6S)-4-methylmalyngolide and (4R,6S)-4-methylmalyngolide bearing a shortened n-nonyl alkyl side chain were prepared in the present study using a ZrCl4-catalysed deprotection/cyclisation as the key step in their asymmetric synthesis. When these were tested for activity against anti-methicillin-resistant Staphylococcus aureus, the MIC increased to 50 µg/mL.


Assuntos
Lactonas/síntese química , Lactonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Lactonas/química , Testes de Sensibilidade Microbiana , Pironas/síntese química , Pironas/química , Pironas/farmacologia
3.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208597

RESUMO

Several natural products (NPs) have displayed varying in vitro activities against methicillin-resistant Staphylococcus aureus (MRSA). However, few of these compounds have not been developed into potential antimicrobial drug candidates. This may be due to the high cost and tedious and time-consuming process of conducting the necessary preclinical tests on these compounds. In this study, cheminformatic profiling was performed on 111 anti-MRSA NPs (AMNPs), using a few orally administered conventional drugs for MRSA (CDs) as reference, to identify compounds with prospects to become drug candidates. This was followed by prioritizing these hits and identifying the liabilities among the AMNPs for possible optimization. Cheminformatic profiling revealed that most of the AMNPs were within the required drug-like region of the investigated properties. For example, more than 76% of the AMNPs showed compliance with the Lipinski, Veber, and Egan predictive rules for oral absorption and permeability. About 34% of the AMNPs showed the prospect to penetrate the blood-brain barrier (BBB), an advantage over the CDs, which are generally non-permeant of BBB. The analysis of toxicity revealed that 59% of the AMNPs might have negligible or no toxicity risks. Structure-activity relationship (SAR) analysis revealed chemical groups that may be determinants of the reported bioactivity of the compounds. A hit prioritization strategy using a novel "desirability scoring function" was able to identify AMNPs with the desired drug-likeness. Hit optimization strategies implemented on AMNPs with poor desirability scores led to the design of two compounds with improved desirability scores.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Quimioinformática/métodos , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos/métodos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072353

RESUMO

The variability of methicillin-resistant Staphylococcus aureus (MRSA), its rapid adaptive response against environmental changes, and its continued acquisition of antibiotic resistance determinants have made it commonplace in hospitals, where it causes the problem of multidrug resistance. In this study, we used molecular topology to develop several discriminant equations capable of classifying compounds according to their anti-MRSA activity. Topological indices were used as structural descriptors and their relationship with anti-MRSA activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones and quinolone-like compounds. Four extra equations were constructed, named DFMRSA1, DFMRSA2, DFMRSA3 and DFMRSA4 (DFMRSA was built in a previous study), all with good statistical parameters, such as Fisher-Snedecor F (>68 in all cases), Wilk's lambda (<0.13 in all cases), and percentage of correct classification (>94% in all cases), which allows a reliable extrapolation prediction of antibacterial activity in any organic compound. The results obtained clearly reveal the high efficiency of combining molecular topology with LDA for the prediction of anti-MRSA activity.


Assuntos
Anti-Infecciosos/química , Análise Discriminante , Descoberta de Drogas/métodos , Algoritmos , Anti-Infecciosos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Modelos Estatísticos , Relação Estrutura-Atividade
5.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072443

RESUMO

As an important zoonotic pathogen, Streptococcus suis (S. suis) infection has been reported to be a causative agent for variety of diseases in humans and animals, especially Streptococcal toxic shock-like syndrome (STSLS), which is commonly seen in cases of severe S. suis infection. STSLS is often accompanied by excessive production of inflammatory cytokines, which is the main cause of death. This calls for development of new strategies to avert the damage caused by STSLS. In this study, we found for the first time that Baicalein, combined with ampicillin, effectively improved severe S. suis infection. Further experiments demonstrated that baicalein significantly inhibited the hemolytic activity of SLY by directly binding to SLY and destroying its secondary structure. Cell-based assays revealed that Baicalein did not exert toxic effects and conferred protection in S. suis-infected cells. Interestingly, compared with ampicillin alone, Baicalein combined with ampicillin resulted in a higher survival rate in mice severely infected with S. suis. At the same time, we found that baicalein can be combined with meropenem against MRSA. In conclusion, these results indicate that baicalein has a good application prospect.


Assuntos
Antibacterianos/farmacologia , Flavanonas/farmacologia , Infecções Estreptocócicas/microbiologia , Streptococcus suis/efeitos dos fármacos , Animais , Antibacterianos/química , Citocinas/biossíntese , Modelos Animais de Doenças , Farmacorresistência Bacteriana/efeitos dos fármacos , Quimioterapia Combinada , Flavanonas/química , Hemólise/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/metabolismo , Infecções Estreptocócicas/patologia , Relação Estrutura-Atividade
6.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071337

RESUMO

Cellulose nanofibers (CNF) isolated from plant biomass have attracted considerable interests in polymer engineering. The limitations associated with CNF-based nanocomposites are often linked to the time-consuming preparation methods and lack of desired surface functionalities. Herein, we demonstrate the feasibility of preparing a multifunctional CNF-zinc oxide (CNF-ZnO) nanocomposite with dual antibacterial and reinforcing properties via a facile and efficient ultrasound route. We characterized and examined the antibacterial and mechanical reinforcement performances of our ultrasonically induced nanocomposite. Based on our electron microscopy analyses, the ZnO deposited onto the nanofibrous network had a flake-like morphology with particle sizes ranging between 21 to 34 nm. pH levels between 8-10 led to the formation of ultrafine ZnO particles with a uniform size distribution. The resultant CNF-ZnO composite showed improved thermal stability compared to pure CNF. The composite showed potent inhibitory activities against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative Salmonella typhi (S. typhi) bacteria. A CNF-ZnO-reinforced natural rubber (NR/CNF-ZnO) composite film, which was produced via latex mixing and casting methods, exhibited up to 42% improvement in tensile strength compared with the neat NR. The findings of this study suggest that ultrasonically-synthesized palm CNF-ZnO nanocomposites could find potential applications in the biomedical field and in the development of high strength rubber composites.


Assuntos
Antibacterianos/química , Arecaceae/química , Celulose/química , Nanocompostos/química , Nanofibras/química , Óxido de Zinco/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Microscopia Eletrônica , Nanocompostos/ultraestrutura , Nanofibras/ultraestrutura , Tamanho da Partícula , Borracha/química , Salmonella/efeitos dos fármacos , Salmonella/crescimento & desenvolvimento , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios X
7.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073939

RESUMO

An amphipathic α-helical peptide, Hp1404, was isolated from the venomous gland of the scorpion Heterometrus petersii. Hp1404 exhibits antimicrobial activity against methicillin-resistant Staphylococcus aureus but is cytotoxic. In this study, we designed antimicrobial peptides by substituting amino acids at the 14 C-terminal residues of Hp1404 to reduce toxicity and improve antibacterial activity. The analog peptides, which had an amphipathic α-helical structure, were active against gram-positive and gram-negative bacteria, particularly multidrug-resistant Acinetobacter baumannii, and showed lower cytotoxicity than Hp1404. N-phenyl-1-naphthylamine uptake and DisC3-5 assays demonstrated that the peptides kill bacteria by effectively permeating the outer and cytoplasmic membranes. Additionally, the analog peptides inhibited biofilm formation largely than Hp1404 at low concentrations. These results suggest that the analog peptides of Hp1404 can be used as therapeutic agents against A. baumannii infection.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escorpiões/química , 1-Naftilamina/análogos & derivados , 1-Naftilamina/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/efeitos adversos , Peptídeos Catiônicos Antimicrobianos/química , Benzotiazóis/metabolismo , Biofilmes/efeitos dos fármacos , Carbocianinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Proteica em alfa-Hélice , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos
8.
BMC Infect Dis ; 21(1): 589, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154550

RESUMO

BACKGROUND: Bloodstream infections due to Staphylococcus aureus cause significant patient morbidity and mortality worldwide. Of major concern is the emergence and spread of methicillin-resistant S. aureus (MRSA) in bloodstream infections, which are associated with therapeutic failure and increased mortality. METHODS: We generated high quality draft genomes from 323 S. aureus blood culture isolates from patients diagnosed with bloodstream infection at the Dartmouth-Hitchcock Medical Center, New Hampshire, USA in 2010-2018. RESULTS: In silico detection of antimicrobial resistance genes revealed that 133/323 isolates (41.18%) carry horizontally acquired genes conferring resistance to at least three antimicrobial classes, with resistance determinants for aminoglycosides, beta-lactams and macrolides being the most prevalent. The most common resistance genes were blaZ and mecA, which were found in 262/323 (81.11%) and 104/323 (32.20%) isolates, respectively. Majority of the MRSA (102/105 isolates or 97.14%) identified using in vitro screening were related to two clonal complexes (CC) 5 and 8. The two CCs emerged in the New Hampshire population at separate times. We estimated that the time to the most recent common ancestor of CC5 was 1973 (95% highest posterior density (HPD) intervals: 1966-1979) and 1946 for CC8 (95% HPD intervals: 1924-1959). The effective population size of CC8 increased until the late 1960s when it started to level off until late 2000s. The levelling off of CC8 in 1968 coincided with the acquisition of SCCmec Type IV in majority of the strains. The plateau in CC8 also coincided with the acceleration in the population growth of CC5 carrying SCCmec Type II in the early 1970s, which eventually leveled off in the early 1990s. Lastly, we found evidence for frequent recombination in the two clones during their recent clonal expansion, which has likely contributed to their success in the population. CONCLUSIONS: We conclude that the S. aureus population was shaped mainly by the clonal expansion, recombination and co-dominance of two major MRSA clones in the last five decades in New Hampshire, USA. These results have important implications on the development of effective and robust strategies for intervention, control and treatment of life-threatening bloodstream infections.


Assuntos
Staphylococcus aureus Resistente à Meticilina/genética , Sepse/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/genética , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Genômica , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Sepse/tratamento farmacológico , Sepse/virologia , Infecções Estafilocócicas/virologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação
9.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071703

RESUMO

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
10.
Int J Nanomedicine ; 16: 4031-4044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140770

RESUMO

Introduction: Topical agents typically remain in the wound site for time duration that are too short to effectively eradicate MRSA tradition formation of BZK that can be maintained within the wound site for longer time periods, should be more effective. Methods: The novel chitosan and poly (D,L-lactide-co-glycoside) nanoparticles loaded with benzalkonium bromide (BZK) were designed, for the promotion wound healing after MRSA infection. The physical characterization of these nanoparticles, as well as their antibacterial activity in vitro, release profile in simulated wound fluid, cell toxicity, anti-biofilm activity, and their ability to improve the skin wound healing in a mouse model were also studied. Results: These novel nanoparticles were found to have a significant antibacterial activity (p<0.01), both in vitro and in vivo test. The stronger anti-biofilm ability of the nanoparticles to inhibit the formation of bacterial biofilms, at a concentration of 3.33 µg/mL, and clear existing bacterial biofilms, at a concentration of 5 mg/mL, compared with its water solution. In addition, significant damage to bacterial cell walls also was found, providing insight into the mechanism of antibacterial activity. Conclusion: Taken together, these results demonstrated the ability of BZK-loaded nanoparticles in the promotion of skin wound healing with MRSA infection. The current findings open a new avenue for nanomedicine development and future clinical applications in the treatment of wounds.


Assuntos
Antibacterianos/farmacologia , Compostos de Benzalcônio/administração & dosagem , Nanopartículas/administração & dosagem , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Compostos de Benzalcônio/farmacocinética , Compostos de Benzalcônio/farmacologia , Biofilmes/efeitos dos fármacos , Quitosana/química , Sistemas de Liberação de Medicamentos , Feminino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos Endogâmicos BALB C , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Álcool de Polivinil/administração & dosagem , Álcool de Polivinil/farmacologia , Infecções Cutâneas Estafilocócicas/microbiologia
11.
Food Chem ; 358: 129833, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933967

RESUMO

This study identified and quantified hydrolysable tannins (HTs) in Terminalia ferdinandiana Exell (Kakadu plum) fruit, freeze dried powder extracted with 80% aqueous acetone (AA) and 80% aqueous acidified ethanol (AAE), using UHPLC-Q/Orbitrap/MS/MS. The vitamin C and ellagic acid were quantified by UHPLC-PDA. A total of seven HTs were identified: corilagin, 3,4,6-tri-O-galloyl-ß-d-glucose, elaeocarpusin, chebulinic acid, chebulagic acid, helioscopin B, and punicalagin, with five classified as ellagitannins. The two extracts AA and AAE, comprised of gallic acid (2.5 and 2.2 mg/g DW), punicalagins α and ß (2.8 and 1.3 mg/g DW), respectively, and both contained ellagic acid (~4 g/100 g DW). These extracts showed high antioxidant properties and strong antimicrobial effects against methicillin-resistant Staphylococcus aureus clinical isolate, Staphylococcus aureus, and Shewanella putrefaciens. These results suggest that Kakadu plum fruit is a rich, edible source of ellagitannins, ellagic acid and vitamin C with potential applications in food, cosmetic and nutraceutical industries.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/farmacologia , Terminalia/química , Antibacterianos/química , Antioxidantes/química , Etanol/química , Liofilização , Frutas/química , Glucosídeos/análise , Glucosídeos/química , Taninos Hidrolisáveis/análise , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Extratos Vegetais/química , Pós , Solventes , Espectrometria de Massas em Tandem
12.
Bone Joint J ; 103-B(5): 908-915, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33934664

RESUMO

AIMS: Periprosthetic joint infections (PJIs) are among the most devastating complications after joint arthroplasty. There is limited evidence on the efficacy of different antiseptic solutions on reducing biofilm burden. The purpose of the present study was to test the efficacy of different antiseptic solutions against clinically relevant microorganisms in biofilm. METHODS: We conducted an in vitro study examining the efficacy of several antiseptic solutions against clinically relevant microorganisms. We tested antiseptic irrigants against nascent (four-hour) and mature (three-day) single-species biofilm created in vitro using a drip-flow reactor model. RESULTS: With regard to irrigant efficacy against biofilms, Povidone-iodine treatment resulted in greater reductions in nascent MRSA biofilms (logarithmic reduction (LR) = 3.12; p < 0.001) compared to other solutions. Bactisure treatment had the greatest reduction of mature Pseudomonas aeruginosa biofilms (LR = 1.94; p = 0.032) and a larger reduction than Vashe or Irrisept for mature Staphylococcus epidermidis biofilms (LR = 2.12; p = 0.025). Pooled data for all biofilms tested resulted in Bactisure and Povidone-iodine with significantly greater reductions compared to Vashe, Prontosan, and Irrisept solutions (p < 0.001). CONCLUSION: Treatment failure in PJI is often due to failure to clear the biofilm; antiseptics are often used as an adjunct to biofilm clearance. We tested irrigants against clinically relevant microorganisms in biofilm in vitro and showed significant differences in efficacy among the different solutions. Further clinical outcome data is necessary to determine whether these solutions can impact PJI outcome in vivo. Cite this article: Bone Joint J 2021;103-B(5):908-915.


Assuntos
Antibacterianos/farmacologia , Anti-Infecciosos Locais/farmacologia , Artroplastia de Substituição , Biofilmes/efeitos dos fármacos , Infecções Relacionadas à Prótese/microbiologia , Infecções Relacionadas à Prótese/prevenção & controle , Ácido Acético/farmacologia , Compostos de Benzalcônio/farmacologia , Betaína/farmacologia , Biguanidas/farmacologia , Clorexidina/análogos & derivados , Clorexidina/farmacologia , Peróxido de Hidrogênio/farmacologia , Técnicas In Vitro , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Povidona-Iodo/farmacologia , Propionibacteriaceae/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Hipoclorito de Sódio/farmacologia , Staphylococcus epidermidis/efeitos dos fármacos
13.
J Med Chem ; 64(11): 7272-7274, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33988992

RESUMO

Halogenated phenazines (HPs) are potent antimicrobial agents. A newly developed halogenated phenazine, HP-29, displays remarkable minimum inhibitory concentration (MIC) of 0.08 µM against methicillin-resistant Staphylococcus aureus, MRSA. HP-29 eradicates preformed biofilm via iron starvation, is nontoxic to mammalian cell lines and is efficacious in wound infection models.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Ferro/química , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Quelantes/química , Quelantes/farmacologia , Quelantes/uso terapêutico , Modelos Animais de Doenças , Halogenação , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Fenazinas/química , Fenazinas/farmacologia , Fenazinas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico
14.
J Med Chem ; 64(11): 7359-7370, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34032114

RESUMO

Novel antibacterial agents capable of efficiently sterilizing intracellular Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) but with low cytotoxicity and low resistance development are quite appealing. In this work, three Ru(II) complexes with photolabile ligands were explored to realize such a goal. Complex 3 (5 µM) can inhibit more than 90% growth of S. aureus/MRSA that has invaded in J774A.1 cells upon visible light irradiation, being much more efficient than vancomycin. In similar conditions, negligible dark- and phototoxicity were found toward the host cells. The bactericidal activity is highly correlated with DNA covalent binding by the Ru(II) fractions generated after ligand photodissociation. Moreover, S. aureus quickly developed resistance toward vancomycin, while negligible resistance toward complex 3 even after 700 generations was obtained. These appealing results may pave a new way for fighting against intracellular antibiotic-resistant pathogens.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/química , Luz , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Rutênio/química , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , DNA/química , DNA/metabolismo , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Ligantes , Fotólise , Coelhos
15.
Methods Mol Biol ; 2296: 351-363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977458

RESUMO

Daptomycin is a cyclic lipopeptide antibiotic with potent activity against gram-positive bacteria. It has a calcium-dependent mechanism of action that disrupts multiple features of the bacterial membrane function. This antibiotic is highly demanded due to its effectiveness against to microorganisms resistant to other antibiotics, including vancomycin-resistant Staphylococcus aureus (VRSA) and methicillin-resistant S. aureus (MRSA). Daptomycin is produced by fermentation of Streptomyces roseosporus, currently identified as Streptomyces filamentosus. However, low fermentation yields and high production costs are reported. This chapter describes a method of strain improvement involving random mutagenesis, rational screening by bioassay, and flask fermentation. The ultimate objective is to select mutants of S. roseosporus overproducing daptomycin in order to design a more cost-effective daptomycin production.


Assuntos
Daptomicina/biossíntese , Streptomyces/metabolismo , Antibacterianos/biossíntese , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Daptomicina/farmacologia , Fermentação/fisiologia , Engenharia Genética/métodos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Mutagênese/genética , Streptomyces/efeitos dos fármacos , Streptomyces/genética
16.
Int J Biol Macromol ; 183: 447-456, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33932414

RESUMO

The preparation of ointments from natural compounds is essential for accelerating infected wounds. This study investigated the effects of topical uses of gold nanoparticles (Au)/perlite (Au/Perl) nanocomposites (NCs) by the help of Urtica dioica extract and its chitosan-capped derivative (Chit) on methicillin-resistant Staphylococcus aureus (MRSA)-infected wound healing in a mouse model. Furthermore, Au/Perl/Chit nanocomposite was prepared using protonated chitosan solution. The physicochemical properties of the as-synthesized nanocomposites were also investigated. The effects of Au/Perl/Chit NC were assessed by antibacterial, histopathological parameters as well as molecular evaluations. Then, they were compared with synthetic agent of mupirocin. The results revealed that Au/Perl NC was mesoporous and spherical in a range of 13-15 nm. Topical administration of Au/Perl/Chit ointment accelerated wound healing by reducing bacteria colonization and wound rate enhancing collagen biosynthesis and re-epithelialization, the expressions of IL-10, PI3K, AKT, bFGF, and COL1A genes, which is in agreement with the obtained results for mupirocin. In conclusion, the results strongly demonstrated that administration of ointments prepared from Au/Perl and Au/Perl/Chit nanocomposites stimulates MRSA-infected wound healing by decreasing the length of healing time and regulating PI3K/AKT/bFGF signaling pathway and is a promising candidate in stimulating MRSA-infected wound regeneration.


Assuntos
Óxido de Alumínio/farmacologia , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Quitosana/farmacologia , Compostos de Ouro/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Dióxido de Silício/farmacologia , Pele/efeitos dos fármacos , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Urtica dioica/metabolismo , Cicatrização/efeitos dos fármacos , Óxido de Alumínio/metabolismo , Animais , Antibacterianos/metabolismo , Antioxidantes/metabolismo , Proliferação de Células/efeitos dos fármacos , Quitosana/análogos & derivados , Quitosana/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/microbiologia , Fibroblastos/patologia , Compostos de Ouro/metabolismo , Química Verde , Masculino , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanopartículas , Nanotecnologia , Transdução de Sinais , Dióxido de Silício/metabolismo , Pele/metabolismo , Pele/microbiologia , Pele/patologia , Infecções Cutâneas Estafilocócicas/metabolismo , Infecções Cutâneas Estafilocócicas/microbiologia , Infecções Cutâneas Estafilocócicas/patologia , Fatores de Tempo
17.
Int J Biol Macromol ; 183: 852-860, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33932416

RESUMO

Growing antibiotic resistance of bacteria is a burning problem of human and veterinary medicine. Expansion and introduction of novel microbicidal therapeutics is highly desirable. However, antibiotic treatment disturbs the balance of physiological microbiota by changing its qualitative and/or quantitative composition, resulting in a number of adverse effects that include secondary infections. Although such dysbiosis may be reversed by the treatment with probiotics, a more attractive alternative is the use of antibiotics that target only pathogens, while sparing the commensals. Here, we describe lysostaphin LSp222, an enzyme produced naturally by Staphylococcus pseudintermedius 222. LSp222 is highly effective against S. aureus, including its multi-drug resistant strains. Importantly, the inhibitory concentration for S. epidermidis, the predominant commensal in healthy human skin, is at least two orders of magnitude higher compared to S. aureus. Such significant therapeutic window makes LSp222 a microbiota-friendly antibacterial agent with a potential application in the treatment of S. aureus-driven skin infections.


Assuntos
Lisostafina/farmacologia , Microbiota/efeitos dos fármacos , Pele/microbiologia , Staphylococcus/enzimologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Pele/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos
18.
Artigo em Inglês | MEDLINE | ID: mdl-33852710

RESUMO

Despite the widespread use of chlorhexidine (CHX) to prevent infection, data regarding the in vitro action of CHX against methicillin-resistant Staphylococcus aureus (MRSA) are limited. Clinical isolates from Hospital das Clinicas, Sao Paulo, Brazil, identified during 2002/2003 and 2012/2013 were studied to describe the susceptibility to CHX and mupirocin, molecular characteristics, and virulence profile of MRSA. Susceptibility test to Mupirocin was performed by the disk diffusion method and to CHX by the agar dilution technique. PCR for virulence genes, mecA gene and Staphylococcal Cassette Chromosome mec (SCCmec) types were investigated as well. Mupirocin- and CHX-resistant isolates were sequenced using the IlluminaTM plataform. Two hundred and sixteen MRSA clinical isolates were evaluated: 154 from infected and 62 from colonized patients. Resistance to mupirocin was observed in four isolates assigned as SCCmec type III and STs (ST05; ST239 and ST105) carrying mupA and blaZ, two of them co-harboring the ileS gene. Only one isolate assigned as SCCmec type III was resistant to CHX (MIC of 8.0 µg.mL-1) and harbored the qacA gene. Resistance to chlorhexidine and mupirocin were found in isolates carrying qacA and mupA in our hospital. Since these genes are plasmid-mediated, this finding draws attention to the potential spread of resistance to mupirocin in our hospital.


Assuntos
Antibacterianos/farmacologia , Clorexidina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Mupirocina/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Bactérias/genética , Brasil , Criança , Pré-Escolar , DNA Bacteriano/genética , Feminino , Hospitais de Ensino , Humanos , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Análise de Sequência de DNA , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Virulência , Adulto Jovem
19.
Molecules ; 26(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799713

RESUMO

Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the design and synthesis of a novel bone-binding antibiotic (BBA-1) and its subsequent structural and functional characterization. The synthesis of BBA-1 was the result of a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90) and the bisphosphonate alendronate (ALN) via a heterobifunctional linker. This was analytically confirmed by HPLC, FT-IR, MS and NMR spectroscopy. BBA-1 showed rapid binding and high affinity to bone mineral in an in vitro hydroxyapatite binding assay. Kirby-Baur assays confirmed that BBA-1 shows a potent antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus comparable to CSA-90. Differentiation of cultured osteoblasts in media supplemented with BBA-1 led to increased alkaline phosphatase expression, which is consistent with the pro-osteogenic activity of CSA-90. Bisphosphonates, such as ALN, are inhibitors of protein prenylation, however, the amine conjugation of ALN to CSA-90 disrupted this activity in an in vitro protein prenylation assay. Overall, these findings support the antimicrobial, bone-binding, and pro-osteogenic activities of BBA-1. The compound and related agents have the potential to ensure lasting activity against osteomyelitis after systemic delivery.


Assuntos
Alendronato/química , Antibacterianos/síntese química , Osteomielite/tratamento farmacológico , Pregnanos/química , Propilaminas/química , Células 3T3 , Alendronato/farmacologia , Animais , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Osso e Ossos/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Difosfonatos/química , Difosfonatos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Pregnanos/farmacologia , Propilaminas/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos
20.
Molecules ; 26(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33923072

RESUMO

The present research aimed to enhance the pharmaceutically active compounds' (PhACs') productivity from Streptomyces SUK 25 in submerged fermentation using response surface methodology (RSM) as a tool for optimization. Besides, the characteristics and mechanism of PhACs against methicillin-resistant Staphylococcus aureus were determined. Further, the techno-economic analysis of PhACs production was estimated. The independent factors include the following: incubation time, pH, temperature, shaker rotation speed, the concentration of glucose, mannitol, and asparagine, although the responses were the dry weight of crude extracts, minimum inhibitory concentration, and inhibition zone and were determined by RSM. The PhACs were characterized using GC-MS and FTIR, while the mechanism of action was determined using gene ontology extracted from DNA microarray data. The results revealed that the best operating parameters for the dry mass crude extracts production were 8.20 mg/L, the minimum inhibitory concentrations (MIC) value was 8.00 µg/mL, and an inhibition zone of 17.60 mm was determined after 12 days, pH 7, temperature 28 °C, shaker rotation speed 120 rpm, 1 g glucose /L, 3 g mannitol/L, and 0.5 g asparagine/L with R2 coefficient value of 0.70. The GC-MS and FTIR spectra confirmed the presence of 21 PhACs, and several functional groups were detected. The gene ontology revealed that 485 genes were upregulated and nine genes were downregulated. The specific and annual operation cost of the production of PhACs was U.S. Dollar (U.S.D) 48.61 per 100 mg compared to U.S.D 164.3/100 mg of the market price, indicating that it is economically cheaper than that at the market price.


Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Preparações Farmacêuticas/isolamento & purificação , Streptomyces/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Fermentação , Humanos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Testes de Sensibilidade Microbiana , Preparações Farmacêuticas/química , Propriedades de Superfície
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