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2.
Antimicrob Agents Chemother ; 65(9): e0097821, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34228543

RESUMO

Rifampicin is an effective drug for treating tuberculosis (TB) but is not used to treat Mycobacterium abscessus infections due to poor in vitro activity. While rifabutin, another rifamycin, has better anti-M. abscessus activity, its activity is far from the nanomolar potencies of rifamycins against Mycobacterium tuberculosis. Here, we asked (i) why is rifabutin more active against M. abscessus than rifampicin, and (ii) why is rifabutin's anti-M. abscessus activity poorer than its anti-TB activity? Comparative analysis of naphthoquinone- versus naphthohydroquinone-containing rifamycins suggested that the improved activity of rifabutin over rifampicin is linked to its less readily oxidizable naphthoquinone core. Although rifabutin is resistant to bacterial oxidation, metabolite and genetic analyses showed that this rifamycin is metabolized by the ADP-ribosyltransferase ArrMab like rifampicin, preventing it from achieving the nanomolar activity that it displays against M. tuberculosis. Based on the identified dual mechanism of intrinsic rifamycin resistance, we hypothesized that rifamycins more potent than rifabutin should contain the molecule's naphthoquinone core plus a modification that blocks ADP-ribosylation at its C-23. To test these predictions, we performed a blinded screen of a diverse collection of 189 rifamycins and identified two molecules more potent than rifabutin. As predicted, these compounds contained both a more oxidatively resistant naphthoquinone core and C-25 modifications that blocked ADP-ribosylation. Together, this work revealed dual bacterial metabolism as the mechanism of intrinsic resistance of M. abscessus to rifamycins and provides proof of concept for the repositioning of rifamycins for M. abscessus disease by developing derivatives that resist both bacterial oxidation and ADP-ribosylation.


Assuntos
Mycobacterium abscessus , Rifamicinas , ADP-Ribosilação , Testes de Sensibilidade Microbiana , Rifabutina/farmacologia , Rifamicinas/farmacologia
3.
Antimicrob Agents Chemother ; 65(9): e0104321, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34228545

RESUMO

Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.


Assuntos
Preparações Farmacêuticas , Rifamicinas , Interações Medicamentosas , Rifabutina/farmacologia , Rifampina/farmacologia
4.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33507146

RESUMO

Introduction. Resistance to rifampin (RIF) in Mycobacterium tuberculosis infection is associated with mutations in the rpoB gene coding for the ß-subunit of RNA polymerase. The contribution of various rpoB mutations to the development and level of RIF resistance remains elusive.Hypothesis/Gap Statement. Various rpoB mutations may be associated with differential levels of RIF resistance.Aim. This study aimed to investigate the relationship between specific rpoB mutations and the MICs of RIF and rifabutin (RFB) against M. tuberculosis.Methodology. Of the 195 clinical isolates, 105 and 90 isolates were randomly selected from isolates resistant to RIF and sensitive to RIF, respectively. The MICs of 12 agents for M. tuberculosis isolates were determined using commercial Sensititre M. tuberculosis MIC plates and the broth microdilution method. Strains were screened for rpoB mutations by DNA extraction, rpoB gene amplification and DNA sequence analysis.Results. One hundred isolates (95.24 %) were found to have mutations in the RIF-resistance-determining region (RRDR) of the rpoB gene. Three rpoB mutations were identified in 90 RIF-susceptible isolates. Out of 105 isolates, 86 (81.90 %) were cross-resistant to both RIF and RFB. The most frequent mutation occurred at codons 450 and 445. We also found a novel nine-nucleotide (ATCATGCAT) deletion (between positions 1543 and 1551) in the rpoB gene in two strains (1.90 %) with resistance to RIF, but susceptibility to RFB. In addition, the mutation frequency at codon 450 was significantly higher in RIF-resistant/RFB-resistant (RIFR/RFBR) strains than in RIFR/RFBS strains (75.58 % versus 21.05 %, P<0.01), whereas the mutation frequency at codon 435 was significantly lower in RIFR/RFBR strains than in RIFR/RFBS strains (1.16 % versus 26.32 %, P<0.01).Conclusion. Our data support previous findings, which reported that various rpoB mutations are associated with differential levels of RIF resistance. The specific mutations in the rpoB gene in RIFR/RFBR isolates differed from those in the RIFR/RFBS isolates. A novel deletion mutation in the RRDR might be associated with resistance to RIF, but not to RFB. Further clinical studies are required to investigate the efficacy of RFB in the treatment of infections caused by M. tuberculosis strains harbouring these mutations.


Assuntos
Antibióticos Antituberculose/farmacologia , Proteínas de Bactérias/genética , RNA Polimerases Dirigidas por DNA/genética , Farmacorresistência Bacteriana/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , China , Humanos , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/isolamento & purificação , Rifabutina/farmacologia , Tuberculose/microbiologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-33468472

RESUMO

Recently, we reported rifabutin hyperactivity against Acinetobacter baumannii We sought to characterize potential interactions between rifabutin and colistin, the last-resort drug for carbapenem-resistant infections. Rifabutin and colistin were synergistic in vitro and in vivo, and low-dose colistin significantly suppressed emergence of resistance to rifabutin. Thus, this combination is a promising therapeutic option for highly resistant A. baumannii infections.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Infecções por Acinetobacter/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Rifabutina/farmacologia , Rifabutina/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-33168614

RESUMO

Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net nonreplicating M. abscessus populations in nutrient-rich and nutrient-starvation conditions, respectively. As single drugs, bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and nonreplicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the bedaquiline-rifabutin combination against nutrient-starved M. abscessus Overall, these in vitro data suggest that bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich data set of differential time- and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Preparações Farmacêuticas , Antibacterianos/farmacologia , Diarilquinolinas , Humanos , Testes de Sensibilidade Microbiana , Nutrientes , Rifabutina/farmacologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-33199387

RESUMO

Staphylococcus epidermidis is a major cause of periprosthetic joint infection (PJI); its intracellular persistence within osteoblasts may compromise therapy if that therapy is not intracellularly active. The intracellular activity of rifampin, rifapentine, and rifabutin was assessed against five rifampin-susceptible and two rifampin-resistant S. epidermidis isolates. Compared to no treatment, treatment resulted in a ≥2-fold log10 reduction of intracellular rifampin-susceptible, but not rifampin-resistant, S. epidermidis These findings show activity of rifampin, rifapentine, and rifabutin against intraosteoblast PJI-associated S. epidermidis.


Assuntos
Infecções Relacionadas à Prótese , Rifampina , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Infecções Relacionadas à Prótese/tratamento farmacológico , Rifabutina/farmacologia , Rifampina/análogos & derivados , Rifampina/farmacologia , Staphylococcus epidermidis
8.
Artigo em Inglês | MEDLINE | ID: mdl-33318008

RESUMO

Mycobacterium abscessus exhibits Arr (ADP-ribosyltransferase)-dependent rifampin resistance. In apparent contrast, rifabutin (RBT) has demonstrated promising activity in M. abscessus infection models, implying that RBT might not be inactivated by Arr. RBT susceptibility testing of M. abscessus Δarr revealed a strongly decreased MIC. Our findings suggest that the efficacy of RBT might be enhanced by rendering RBT resilient to Arr-dependent modification or by blocking M. abscessus Arr activity.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , ADP Ribose Transferases , Humanos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium abscessus/genética , Rifabutina/farmacologia , Rifampina/farmacologia
10.
Int J Biol Macromol ; 163: 1787-1797, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950529

RESUMO

The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.


Assuntos
Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Betacoronavirus/enzimologia , COVID-19 , Infecções por Coronavirus/virologia , Fidaxomicina/química , Fidaxomicina/farmacologia , Humanos , Ivermectina/química , Ivermectina/farmacologia , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/virologia , Rifabutina/química , Rifabutina/farmacologia , Rifampina/análogos & derivados , Rifampina/química , Rifampina/farmacologia , SARS-CoV-2 , Replicação Viral/efeitos dos fármacos
11.
J Antimicrob Chemother ; 75(12): 3552-3562, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32869081

RESUMO

BACKGROUND: Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE. OBJECTIVES: To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates. METHODS: Two hundred and ninety-three carbapenem-resistant A. baumannii clinical isolates collected from Europe, the USA and Asia during 2017-19 were used for MIC determination. Sequencing/genotyping of fhuE, rpoB and arr-2 genes in isolates with elevated rifabutin MIC combined with genetic engineering and gene expression quantification was used to characterize rifabutin's mode of action and resistance mechanisms. RESULTS: Rifabutin showed excellent activity on the strain panel, with an MIC50/90 of 0.008/1 mg/L, and was superior to all other antibiotics tested, including colistin, tigecycline and cefiderocol (MIC90 of 8 mg/L). Rifabutin remained active on resistant subpopulations, including strains resistant to the siderophore-drug conjugate cefiderocol (MIC90 of 2 mg/L, n = 23). At least two independent resistance mechanisms were required to abolish rifabutin activity, which is in line with the dose-dependent mutational resistance frequency reaching 10-9 at rifabutin concentrations at or above 2 mg/L. CONCLUSIONS: This study demonstrated the potent activity of rifabutin against carbapenem-resistant A. baumannii. We propose that FhuE-mediated active uptake of rifabutin enables activity against rifampicin-resistant isolates. To achieve clinically meaningful strain coverage and to avoid rapid resistance development, rifabutin concentrations ≥2 mg/L are required, something rifabutin oral formulations cannot deliver.


Assuntos
Acinetobacter baumannii , Acinetobacter baumannii/genética , Antibacterianos/farmacologia , Ásia , Carbapenêmicos/farmacologia , Farmacorresistência Bacteriana Múltipla , Europa (Continente) , Testes de Sensibilidade Microbiana , Rifabutina/farmacologia
12.
Antimicrob Agents Chemother ; 64(11)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32816730

RESUMO

Mycobacterium abscessus is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. In this context, rifabutin (RFB) has been shown to be active against M. abscessus and has raised renewed interest in using rifamycins for the treatment of M. abscessus pulmonary diseases. Here, we compared the in vitro and in vivo activity of RFB against the smooth and rough variants of M. abscessus, differing in their susceptibility profiles to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains in vitro, suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracellular mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from M. abscessus-induced killing. This was corroborated by a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against M. abscessus both in vitro and in vivo, further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Animais , Antibacterianos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Rifabutina/farmacologia , Peixe-Zebra
13.
J Antibiot (Tokyo) ; 73(12): 868-872, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32651464

RESUMO

The expanded microbiological evaluation of a series of rifastures, novel spiropiperidyl rifamycin derivatives, against clinically relevant ESKAPE bacteria has identified several analogs with promising in vitro bioactivities against antibiotic-resistant strains of Enterococcus faecium and Staphylococcus aureus. Thirteen of the rifastures displayed minimum inhibitory concentrations (MICs) below 1 µg/ml against the methicillin- and vancomycin-resistant forms of S. aureus and E. faecium (MRSA, VRSA, VRE). Aryl-substituted rifastures 1, 11, and 12 offered the greatest bioactivity, with MICs reaching ≤0.063 µg ml-1 for these human pathogens. Further analysis indicates that diphenyl rifasture 1 had greater antibiofilm activity against S. aureus and lower cytotoxicity in mammalian HEK cells than rifabutin.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Rifabutina/análogos & derivados , Farmacorresistência Bacteriana , Enterococcus faecium/efeitos dos fármacos , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Rifabutina/farmacologia , Rifamicinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Nat Microbiol ; 5(9): 1134-1143, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32514072

RESUMO

Industry screens of large chemical libraries have traditionally relied on rich media to ensure rapid bacterial growth in high-throughput testing. We used eukaryotic, nutrient-limited growth media in a compound screen that unmasked a previously unknown hyperactivity of the old antibiotic, rifabutin (RBT), against highly resistant Acinetobacter baumannii. In nutrient-limited, but not rich, media, RBT was 200-fold more potent than rifampin. RBT was also substantially more effective in vivo. The mechanism of enhanced efficacy was a Trojan horse-like import of RBT, but not rifampin, through fhuE, only in nutrient-limited conditions. These results are of fundamental importance to efforts to discover antibacterial agents.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Nutrientes/metabolismo , Rifabutina/farmacologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/genética , Animais , Proteínas de Bactérias/efeitos dos fármacos , Proteínas de Bactérias/genética , Colistina/farmacologia , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/genética , Deleção de Genes , Regulação Bacteriana da Expressão Gênica , Ensaios de Triagem em Larga Escala , Masculino , Camundongos , Camundongos Endogâmicos C3H , Testes de Sensibilidade Microbiana , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Rifampina/farmacologia
15.
Bioorg Med Chem Lett ; 30(11): 127168, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32273216

RESUMO

Fourteen ansamycin derivatives including seven new herbimycins G-L (1-6) and divergolide O (7), and seven known analogues were isolated from a culture broth of the marine-derived Streptomyces sp. SCSGAA 0027. Their complete structures were determined by detailed analysis of spectroscopic data and quantum chemical calculations. Compounds 1-5 and 7 featured an additional eight-membered O-heterocycle that has rarely been reported for ansamycins, and the Z,Z- and E,E-configurations for Δ2,Δ4 were reported for the first time in geldanamycin analogues. Compound 1 exhibited weak inhibition activity towards Hsp90α with an IC50 value of 96 µM, 2-5 showed mild cytotoxicity against four human cancer cell lines with IC50 values ranging from 13 µM to 86 µM, and 7 had moderate anti-HSV-1 activity with an IC50 value of 19 µM and very weak cytotoxicity towards Vero cell. The possible biosynthetic pathways for 1-5 were proposed. And their structure-bioactivity relationship was also discussed.


Assuntos
Antivirais/química , Rifabutina/análogos & derivados , Streptomyces/química , Antivirais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Herpesvirus Humano 1/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Rifabutina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Streptomyces/metabolismo , Relação Estrutura-Atividade
16.
J Nat Prod ; 83(4): 965-971, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32182062

RESUMO

Kendomycin is a small-molecule natural product that has gained significant attention due to reported cytotoxicity against pathogenic bacteria and fungi as well as a number of cancer cell lines. Despite significant biomedical interest and attempts to reveal its mechanism of action, the cellular target of kendomycin remains disputed. Herein it is shown that kendomycin induces cellular responses indicative of cation stress comparable to the effects of established iron chelators. Furthermore, addition of excess iron and copper attenuated kendomycin cytotoxicity in bacteria, yeast, and mammalian cells. Finally, NMR analysis demonstrated a direct interaction with cations, corroborating a close link between the observed kendomycin polypharmacology across different species and modulation of iron and/or copper levels.


Assuntos
Antibacterianos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Quelantes/farmacologia , Fungos/efeitos dos fármacos , Rifabutina/análogos & derivados , Cátions , Linhagem Celular , Cobre/metabolismo , Ferro/metabolismo , Leupeptinas/farmacologia , Testes de Sensibilidade Microbiana , Mutagênese , Rifabutina/farmacologia , Leveduras/efeitos dos fármacos
17.
J Antimicrob Chemother ; 75(6): 1466-1473, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32125419

RESUMO

BACKGROUND: Targeting biofilm-embedded and intraosteoblastic Staphylococcus aureus, rifampicin gained a pivotal role in bone and joint infection (BJI) treatment. Two other rifamycins, rifabutin and rifapentine, may represent better-tolerated alternatives, but their activity against bacterial reservoirs associated with BJI chronicity has never been evaluated. OBJECTIVES: To evaluate the activities of rifampicin, rifabutin and rifapentine in osteoblast infection models. METHODS: Using three S. aureus isolates, rifamycins were compared regarding: (i) their intracellular activity in 'acute' (24 h) and 'chronic' (7 days) osteoblast infection models at 0.1× MIC, 1× MIC, 10× MIC and 100× MIC, while impacting infection-induced cytotoxicity (MTT assay), intracellular phenol-soluble modulin (PSM) secretion (RT-PCR), resistance selection and small colony variant (SCV) emergence; and (ii) their minimal biofilm eradication concentration (MBEC) and their MIC to prevent biofilm formation (bMIC). RESULTS: At 0.1× MIC, only rifabutin significantly reduced intracellular inoculum and PSM secretion. All rifamycins allowed a 50% reduction of intraosteoblastic inoculum at higher concentrations, with no difference between acute and chronic infection models, while reducing infection-induced cytotoxicity and PSM secretion. Dose-dependent emergence of intracellular SCVs was observed for all molecules. No intracellular emergence of resistance was detected. bMICs were equivalent for all molecules, but MBEC90s of rifapentine and rifabutin were 10- to 100-fold lower than those of rifampicin, respectively. CONCLUSIONS: All rifamycins are efficient in reducing the S. aureus intraosteoblastic reservoir while limiting infection-induced cytotoxicity, with a higher activity of rifabutin at low concentrations. All molecules prevent biofilm formation, but only rifapentine and rifabutin consistently reduce formed biofilm-embedded bacteria for all isolates. The activity of rifabutin at lower doses highlights its therapeutic potential.


Assuntos
Rifamicinas , Infecções Estafilocócicas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes , Humanos , Testes de Sensibilidade Microbiana , Rifabutina/farmacologia , Rifamicinas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus
18.
Artigo em Inglês | MEDLINE | ID: mdl-31767722

RESUMO

There is no reliable cure for Mycobacterium abscessus lung disease. Rifampin is not used clinically due to poor in vitro potency. In contrast, we have shown that rifabutin, another approved rifamycin used to treat tuberculosis, is potent in vitro against M. abscessus Here, we report that rifabutin is as active as clarithromycin against M. abscessus K21 in NOD.CB17-Prkdcscid/NCrCrl mice. This suggests that rifabutin should be considered a repurposing candidate for patients with M. abscessus disease.


Assuntos
Antibacterianos/farmacologia , Pneumopatias/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium abscessus/efeitos dos fármacos , Rifabutina/farmacologia , Animais , Antibacterianos/química , Claritromicina/farmacologia , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Feminino , Humanos , Pneumopatias/microbiologia , Camundongos , Camundongos Endogâmicos NOD , Infecções por Mycobacterium não Tuberculosas/microbiologia , Rifabutina/química
19.
Eur J Pharm Biopharm ; 147: 38-44, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31790800

RESUMO

Tuberculosis is a leading cause of death worldwide. Although the development of new antimycobacterial drugs is an obvious and necessary strategy to address the disease, improving the therapeutic performance of drugs already approved constitutes a valuable alternative approach. As the lung is the most affected organ, where M. tuberculosis is able to survive and proliferate, the direct pulmonary delivery of antitubercular drugs comprises a highly promising therapeutic strategy. In this work, spray-dried locust bean gum (LBG) microparticles were used to deliver a combination of two first line antitubercular drugs, isoniazid (INH) and rifabutin (RFB), to the alveolar zone, where macrophages hosting the bacteria reside. LBG is expected to mediate favoured macrophage uptake of microparticles, leading to enhanced therapeutic effect. The therapeutic effect of LBG/INH/RFB microparticles was evaluated in a murine model infected with M. tuberculosis, strain H37Rv and compared with oral co-therapy of INH and RFB in the free form. The pulmonary administration of LBG/INH/RFB microparticles 5 times per week was the only treatment schedule that provided negative growth index values in lung (-0.22), spleen (-0.14) and liver (-0.26) even using a lower therapeutic dose for both antibiotics. For the control group, the respective values were +1.95, +0.75 and +0.96.


Assuntos
Galactanos/química , Isoniazida/administração & dosagem , Mananas/química , Gomas Vegetais/química , Rifabutina/administração & dosagem , Tuberculose/tratamento farmacológico , Administração Oral , Animais , Antituberculosos/administração & dosagem , Antituberculosos/farmacologia , Modelos Animais de Doenças , Combinação de Medicamentos , Isoniazida/farmacologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Microesferas , Mycobacterium tuberculosis/efeitos dos fármacos , Rifabutina/farmacologia , Tuberculose/microbiologia
20.
J Nat Prod ; 82(12): 3366-3371, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31765156

RESUMO

Three new kendomycin analogues, kendomycins B-D (1-3), were discovered from the marine-derived actinomycete Verrucosispora sp. SCSIO 07399. The structures of 1-3 were elucidated using diverse spectroscopic data analyses, X-ray crystallography, and semisynthetic derivatization. In vitro antimicrobial assays revealed that 1-3 all display good antibacterial activities against six Gram-positive bacteria with MIC values ranging from 0.5 to 8.0 µg/mL. Additionally, 1-3 were found to be moderately cytotoxic against MGC803, A549, HeLa, HepG2, MCF-7, and RKO human tumor cell lines; IC50 values ranged from 2.2 to 44 µM.


Assuntos
Antineoplásicos/farmacologia , Biologia Marinha , Micromonosporaceae/química , Rifabutina/análogos & derivados , Antibacterianos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Estrutura Molecular , Rifabutina/química , Rifabutina/farmacologia , Análise Espectral/métodos
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