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1.
Bioorg Med Chem Lett ; 24(19): 4689-4693, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25193234

RESUMO

Inhibitors of Staphylococcus aureus biotin protein ligase (SaBPL) are generated by replacing the acyl phosphate group of biotinyl-5'-AMP with either a 1,2,3-triazole (see 5/10a/10b) or a 1,2,4-oxadiazole (see 7) bioisostere. Importantly, the inhibitors are inactive against the human BPL. The nature of the 5-substituent in the component benzoxazolone of the optimum 1,2,3-triazole series is critical to activity, where this group binds in the ATP binding pocket of the enzyme.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Biotina/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Ligases/antagonistas & inibidores , Organofosfatos/farmacologia , Proteínas de Bactérias/metabolismo , Biotina/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Ligases/metabolismo , Modelos Moleculares , Estrutura Molecular , Organofosfatos/síntese química , Organofosfatos/química , Staphylococcus aureus/enzimologia
2.
Sci Transl Med ; 14(662): eabj2381, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36103517

RESUMO

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 µg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.


Assuntos
Anti-Infecciosos , Infecções por Bactérias Gram-Positivas , Staphylococcus aureus Resistente à Meticilina , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/farmacologia , Biofilmes , Glicopeptídeos/farmacologia , Glicopeptídeos/uso terapêutico , Lipoglicopeptídeos/uso terapêutico , Mamíferos , Camundongos , Testes de Sensibilidade Microbiana , Streptococcus pneumoniae , Vancomicina/farmacologia , Vancomicina/uso terapêutico
3.
Trends Microbiol ; 27(4): 339-354, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30448198

RESUMO

The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have paradoxically improved levels of survival than at the OBC due to a decreased net rate of cell death. Despite extensive observational reports of this effect in different microorganisms, its underlying mode of action is not well understood. Although aspects of the Eagle effect resemble persistence, there is strong evidence that these phenomena are substantially different phenotypic responses to antibiotic treatment. We present an overview of the microorganism and antimicrobial combinations in which the Eagle effect has been observed. Proposed underlying mechanism(s) are assessed, and the Eagle effect and microbial persistence are compared and contrasted. The clinical relevance of the Eagle effect is reviewed, incorporating evidence from experimental in vitro and in vivo studies, as well as clinical reports.


Assuntos
Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Animais , Anti-Infecciosos/metabolismo , Bactérias/metabolismo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Farmacorresistência Bacteriana , Tolerância a Medicamentos/genética , Tolerância a Medicamentos/fisiologia , Fungos/metabolismo , Regulação Bacteriana da Expressão Gênica , Humanos , Testes de Sensibilidade Microbiana
4.
Front Microbiol ; 9: 1420, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30013531

RESUMO

Vancomycin was bactericidal against Clostridium difficile at eightfold the minimum inhibitory concentration (MIC) using a traditional minimum bactericidal concentration (MBC) assay. However, at higher concentrations up to 64 × MIC, vancomycin displayed a paradoxical "more-drug-kills-less" Eagle effect against C. difficile. To overcome challenges associated with performing the labor-intensive agar-based MBC method under anaerobic growth conditions, we investigated an alternative more convenient ATP-bioluminescence assay to assess the Eagle effect in C. difficile. The commercial BacTiter-GloTM assay is a homogenous method to determine bacterial viability based on quantification of bacterial ATP as a marker for metabolic activity. The ATP-bioluminescence assay was advantageous over the traditional MBC-type assay in detecting the Eagle effect because it reduced assay time and was simple to perform; measurement of viability could be performed in less than 10 min outside of the anaerobic chamber. Using this method, we found C. difficile survived clinically relevant, high concentrations of vancomycin (up to 2048 µg/mL). In contrast, C. difficile did not survive high concentrations of metronidazole or fidaxomicin. The Eagle effect was also detected for telavancin, but not for teicoplanin, dalbavancin, oritavancin, or ramoplanin. All four pathogenic strains of C. difficile tested consistently displayed Eagle effect resistance to vancomycin, but not metronidazole or fidaxomicin. These results suggest that Eagle effect resistance to vancomycin in C. difficile could be more prevalent than previously appreciated, with potential clinical implications. The ATP-Bioluminescence assay can thus be used as an alternative to the agar-based MBC assay to characterize the Eagle effect against a variety of antibiotics, at a wide-range of concentrations, with much greater throughput. This may facilitate improved understanding of Eagle effect resistance and promote further research to understand potential clinical relevance.

5.
J Med Chem ; 61(24): 11349-11371, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30468386

RESUMO

Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis, and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that antitubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here, we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazooxazines. Synthetic analogues with a novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed and synthesized, and structure-activity relationships were generated. Selected derivatives had potent antiparasitic and antitubercular activity while maintaining drug-like properties such as low cytotoxicity, good metabolic stability in liver microsomes and high apparent permeability across Caco-2 cells. The kinetic solubility of the new bicyclic derivatives varied and was found to be a key parameter for future optimization. Taken together, these results suggest that promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development.


Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Animais , Antiparasitários/síntese química , Antituberculosos/síntese química , Células CACO-2 , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Entamoeba histolytica/efeitos dos fármacos , Giardia lamblia/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/efeitos dos fármacos , Nitroimidazóis/farmacologia , Relação Estrutura-Atividade
6.
J Med Chem ; 60(18): 7636-7657, 2017 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-28463485

RESUMO

Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis. In this review, we summarize different classes of nitroimidazoles that have been described in the literature in the past five years, from approved drugs and clinical candidates to examples undergoing preclinical or early stage development. The relatively "nonspecific" mode of action and resistance mechanisms of nitromidazoles are discussed, and contemporary strategies to facilitate nitroimidazole drug development are highlighted.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Doenças Transmissíveis/tratamento farmacológico , Nitroimidazóis/química , Nitroimidazóis/uso terapêutico , Doenças Parasitárias/tratamento farmacológico , Animais , Anti-Infecciosos/farmacologia , Bactérias/efeitos dos fármacos , Humanos , Nitroimidazóis/farmacologia
7.
J Med Chem ; 58(13): 5164-85, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25760275

RESUMO

In the past decade Clostridium difficile has become a bacterial pathogen of global significance. Epidemic strains have spread throughout hospitals, while community acquired infections and other sources ensure a constant inoculation of spores into hospitals. In response to the increasing medical burden, a new C. difficile antibiotic, fidaxomicin, was approved in 2011 for the treatment of C. difficile-associated diarrhea. Rudimentary fecal transplants are also being trialed as effective treatments. Despite these advances, therapies that are more effective against C. difficile spores and less damaging to the resident gastrointestinal microbiome and that reduce recurrent disease are still desperately needed. However, bringing a new treatment for C. difficile infection to market involves particular challenges. This review covers the current drug discovery pipeline, including both small molecule and biologic therapies, and highlights the challenges associated with in vitro and in vivo models of C. difficile infection for drug screening and lead optimization.


Assuntos
Antibacterianos/uso terapêutico , Clostridioides difficile/efeitos dos fármacos , Descoberta de Drogas , Enterocolite Pseudomembranosa/tratamento farmacológico , Enterocolite Pseudomembranosa/microbiologia , Humanos
8.
Eur J Med Chem ; 101: 96-102, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26117821

RESUMO

Metronidazole has been used clinically for over 50 years as an antiparasitic and broad-spectrum antibacterial agent effective against anaerobic bacteria. However resistance to metronidazole in parasites and bacteria has been reported, and improved second-generation metronidazole analogues are needed. The copper catalysed Huigsen azide-alkyne 1,3-dipolar cycloaddition offers a way to efficiently assemble new libraries of metronidazole analogues. Several new metronidazole-triazole conjugates (Mtz-triazoles) have been identified with excellent broad spectrum antimicrobial and antiparasitic activity targeting Clostridium difficile, Entamoeba histolytica and Giardia lamblia. Cross resistance to metronidazole was observed against stable metronidazole resistant C. difficile and G. lamblia strains. However for the most potent Mtz-triazoles, the activity remained in a therapeutically relevant window.


Assuntos
Antibacterianos/farmacologia , Antiparasitários/farmacologia , Clostridioides difficile/efeitos dos fármacos , Metronidazol/química , Metronidazol/farmacologia , Parasitos/efeitos dos fármacos , Triazóis/química , Triazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antiparasitários/síntese química , Antiparasitários/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Entamoeba histolytica/efeitos dos fármacos , Giardia lamblia/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
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