RESUMO
The continuous emergence of resistant bacteria has become a major worldwide health threat. The current development of new antibacterials has lagged far behind. To discover reagents to fight against resistant bacteria, we initiated a chemical approach by synthesizing and screening a small molecule library, reminiscent of the polycyclic indole alkaloids. Indole alkaloids are a class of structurally diverse natural products, many of which were isolated from plants that have been used as traditional medicine for millennia. Specifically, we adapted an evolutionarily conserved biosynthetic strategy and developed a concise and unified diversity synthesis pathway. Using this pathway, we synthesized 120 polycyclic indolines that contain 26 distinct skeletons and a wide variety of functional groups. A tricyclic indoline, Of1, was discovered to selectively potentiate the activity of ß-lactam antibiotics in multidrug-resistant methicillin-resistant Staphylococcus aureus (MRSA), but not in methicillin-sensitive S. aureus. In addition, we found that Of1 itself does not have antiproliferative activity but can resensitize several MRSA strains to the ß-lactam antibiotics that are widely used in the clinic, such as an extended-spectrum ß-lactam antibiotic amoxicillin/clavulanic acid and a first-generation cephalosporin cefazolin. These data suggest that Of1 is a unique selective resistance-modifying agent for ß-lactam antibiotics, and it may be further developed to fight against resistant bacteria in the clinic.
Assuntos
Antibacterianos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Compostos Policíclicos/síntese química , Compostos Policíclicos/farmacologia , beta-Lactamas/farmacologia , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Catálise/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Ouro/química , Células Hep G2 , Humanos , Indóis/química , Meticilina/farmacologia , Testes de Sensibilidade Microbiana , Compostos Policíclicos/químicaRESUMO
Antibiotic-resistant bacterial infections have seen a marked increase in recent years, while antibiotic discovery has waned. Resistance-modifying agents (RMA) offer an intriguing alternative strategy to fight against resistant bacteria. Here we report the discovery, antibiotic profiling, and structure-activity relationships of a novel class of RMAs, tetracyclic indolines. These selectively potentiate ß-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) without antibacterial or ß-lactamase inhibitory activity on their own. The most potent analogue, 6a, showed strong potentiation of amoxicillin/clavulanic acid in a variety of hospital-acquired and community-acquired MRSA strains with low mammalian toxicity. These compounds may be further developed to extend the clinic life span of ß-lactam antibiotics.
Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Indóis/farmacologia , Tetraciclinas/farmacologia , beta-Lactamas/agonistas , Animais , Antibacterianos/farmacologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Sinergismo Farmacológico , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Relação Estrutura-Atividade , beta-Lactamas/metabolismoRESUMO
Previously we discovered a tricyclic indoline, N-[2-(6-bromo-4-methylidene-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)ethyl]-4-chlorobenzene-1-sulfonamide (1, Of1), from bioinspired synthesis of a highly diverse polycyclic indoline alkaloid library, that selectively resensitizes methicillin-resistant Staphylococcus aureus strains to ß-lactam antibiotics. Herein, we report a thorough structure-activity relationship investigation of 1, which identified regions of 1 that tolerate modifications without compromising activity and afforded the discovery of a more potent analogue with reduced mammalian toxicity.