RESUMEN
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.
Asunto(s)
Antituberculosos/farmacología , Nitrofuranos/química , Nitrofuranos/farmacología , Animales , Antituberculosos/química , Antituberculosos/farmacocinética , Chlorocebus aethiops , Femenino , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Nitrofuranos/farmacocinética , Células VeroRESUMEN
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.
Asunto(s)
Antibacterianos/aislamiento & purificación , Antibacterianos/farmacología , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Descubrimiento de Drogas/métodos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Microbiota/genética , Antibacterianos/síntesis química , Antibacterianos/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Humanos , Lipopéptidos/síntesis química , Lipopéptidos/química , Lipopéptidos/genética , Lipopéptidos/farmacología , Staphylococcus aureus Resistente a Meticilina/enzimología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Péptido Sintasas/genética , beta-Lactamas/agonistas , beta-Lactamas/metabolismoRESUMEN
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.
Asunto(s)
Enterococcus faecium , Infecciones por Bacterias Grampositivas , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiologíaRESUMEN
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.