RESUMO
Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19-C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.
RESUMO
The protracted global COVID-19 pandemic urges the development of new drugs against the causative agent SARS-CoV-2. The clinically used glycopeptide antibiotic, teicoplanin, emerged as a potential antiviral, and its efficacy was improved with lipophilic modifications. This prompted us to prepare new lipophilic apocarotenoid conjugates of teicoplanin, its pseudoaglycone and the related ristocetin aglycone. Their antiviral effect was tested against SARS-CoV-2 in Vero E6 cells, using a cell viability assay and quantitative PCR of the viral RNA, confirming their micromolar inhibitory activity against viral replication. Interestingly, two of the parent apocarotenoids, bixin and ß-apo-8'carotenoic acid, exerted remarkable anti-SARS-CoV-2 activity. Mechanistic studies involved cathepsin L and B, as well as the main protease 3CLPro, and the results were rationalized by computational studies. Glycopeptide conjugates show dual inhibitory action, while apocarotenoids have mostly cathepsin B and L affinity. Since teicoplanin is a marketed antibiotic and the natural bixin is an approved, cheap and widely used red colorant food additive, these readily available compounds and their conjugates as potential antivirals are worthy of further exploration.
RESUMO
Antibiotic resistance is one of the major challenges in healthcare of our time. To meet this challenge, we designed and prepared guanidine and lipophilic guanidine derivatives of the glycopeptide antibiotic teicoplanin to armed them with activity against the most threatening nosocomial bacteria, multiresistant enterococci. From teicoplanin and its pseudoaglycone, a series of N-terminal guanidine derivatives have been prepared with free and amide C-terminal parts. Six aliphatic and aromatic lipophilic carbodiimides were prepared and used for the synthesis of lipophilic guanidine teicoplanin conjugates. All new N-terminal guanidine antibiotics showed high activity against a standard panel of Gram-positive bacteria. Four selected derivatives displayed excellent antibacterial activity against a series of nosocomial VanA Enterococcus faecium strains.
Assuntos
Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Glicopeptídeos/farmacologia , Guanidinas/farmacologia , Teicoplanina/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana/métodosAssuntos
Anti-Infecciosos/uso terapêutico , Úlcera de Buruli/terapia , Desbridamento , Mycobacterium ulcerans , Osteomielite/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/terapia , Adolescente , Distribuição por Idade , Idoso , Amicacina/uso terapêutico , Úlcera de Buruli/tratamento farmacológico , Úlcera de Buruli/epidemiologia , Úlcera de Buruli/cirurgia , Criança , Terapia Combinada , Quimioterapia Combinada , Feminino , Humanos , Metronidazol/uso terapêutico , Mycobacterium ulcerans/efeitos dos fármacos , Rifampina/uso terapêutico , Estreptomicina/uso terapêuticoAssuntos
Anti-Infecciosos/uso terapêutico , Complicações do Diabetes/microbiologia , Diabetes Gestacional , Infecções/complicações , Infecções/microbiologia , Neoplasias/prevenção & controle , Vaginose Bacteriana/complicações , Anticarcinógenos/uso terapêutico , Asma/microbiologia , Doença Crônica , Progressão da Doença , Quimioterapia Combinada , Feminino , Humanos , Infecções/tratamento farmacológico , Infertilidade Feminina/microbiologia , Masculino , Neoplasias/virologia , Doenças Periodontais/microbiologia , Pneumonia Bacteriana/complicações , Gravidez , Gravidez Ectópica/microbiologia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Infecções Tumorais por Vírus/tratamento farmacológico , Vaginose Bacteriana/microbiologiaAssuntos
Antibacterianos/uso terapêutico , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Microscopia/métodos , Periodontite/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Vaginose Bacteriana/tratamento farmacológico , Clindamicina/administração & dosagem , Congressos como Assunto , Quimioterapia Combinada , Feminino , Infecções por HIV/prevenção & controle , Humanos , Metronidazol/administração & dosagem , Nistatina/administração & dosagem , Gravidez , Fatores de Risco , Sulfametazina/administração & dosagem , Sulfonamidas/administração & dosagem , Fatores de TempoRESUMO
In 1997 a Finnish group speculated on the presence of nanobacteria in vaccines. In 2001, a report on the identification of nanobacteria in a number of vaccines attracted much attention. Experiments indicated that viable nanobacteria are excreted via urine. Their extreme survivability suggests that prior to discussing any possible contamination of vaccines, sources and routes of natural infection need to be examined. In view of 30,000,000 HIV infections in sub-Saharan Africa, the recently reported occurrence of nanobacteria in HIV-infected patients deserves concern. Clearly, it could indicate the origin of a giant reservoir and dissemination cycle. Here we discuss novel therapeutic strategies to prevent or reduce nanobacterial infection. In regard of the rapid progress in this field, we start with a brief introductory summary, and analyze possible implications.
Assuntos
Infecções Bacterianas/complicações , Infecções Bacterianas/terapia , Infecções por HIV/complicações , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/terapia , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções Bacterianas/microbiologia , Cálcio/metabolismo , Doença Crônica , Infecções por HIV/epidemiologia , Humanos , Fatores de Risco , África do Sul/epidemiologiaRESUMO
Comparative, in vivo, human, prospective, single blind, clinical and microbiological diagnoses based and randomised study of the treatment of uncomplicated bacterial vaginosis with two forms of combined (metronidazole + nystatin + sulfadimidin) vaginal suppositories (laminated and mixed containing the same ingredients) and the standard preparations available in the Hungarian market (Dalacin vaginal cream and Klion vaginal suppository). The examinations involved 60 volunteers and were performed in the Gynecological Outpatient Clinic of the Council of Erd, the microbiological samples were examined at Saint Rókus Hospital in Budapest. The combined treatment was better tolerated and resulted in normal vaginal pH significantly more often at the same rate of recovery. The combined treatment is simultaneously effective in cases of the most prevalent coinfections too.