RESUMO
Hospital-acquired infections, caused by ESKAPE bacteria, are a challenging global public health concern, in part due to the emergence of drug-resistant strains. While profiling a diverse set of compounds for in vitro activity versus this class of bacteria, we noted that the benzothiophene JSF-2827 exhibited promising antibacterial activity against Enterococcus faecium. A hit evolution campaign ensued, involving the design, synthesis, and biological assay of analogues designed to address early issues such as a short mouse liver microsome half-life and a modest mouse pharmacokinetic profile. Among these derivatives, JSF-3269 was found to exhibit an enhanced profile and in vivo efficacy in an immunocompetent mouse model of acute, drug-resistant E. faecium infection. The findings suggest a rationale for the further evolution of this promising series to afford a novel therapeutic strategy to treat drug-resistant E. faecium infection.
Assuntos
Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Testes de Sensibilidade Microbiana , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologiaRESUMO
The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MICâ¯=â¯0.019-0.20⯵M) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC50â¯=â¯40->120⯵M) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MICâ¯=â¯0.019⯵M) and Vero cell cytotoxicity (CC50â¯>â¯120⯵M). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.
Assuntos
Antituberculosos/farmacologia , Nitrofuranos/química , Nitrofuranos/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Chlorocebus aethiops , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrofuranos/farmacocinética , Células VeroRESUMO
The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin 17S. Compared to humimycin A, 17S is a more potent ß-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE), and did not lead to any detectable resistance when used in combination with a ß-lactam. Combinations of ß-lactam and humimycin 17S provide a potentially useful long-term MRSA regimen.
Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Microbiota , Staphylococcus aureus/efeitos dos fármacos , beta-Lactamas/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Farmacorresistência Bacteriana Múltipla/genética , Sinergismo Farmacológico , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Testes de Sensibilidade Microbiana , Modelos Moleculares , Mutação , Proteínas de Transferência de Fosfolipídeos/química , Proteínas de Transferência de Fosfolipídeos/genética , Staphylococcus aureus/genética , Relação Estrutura-AtividadeRESUMO
Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonribosomal peptide synthetase gene clusters from human-associated bacteria, we identified the humimycins. These antibiotics inhibit lipid II flippase and potentiate ß-lactam activity against methicillin-resistant Staphylococcus aureus in mice, potentially providing a new treatment regimen.