RESUMO
The rising prevalence of multidrug-resistant bacteria is an urgent health crisis that can only be countered through renewed investment in the discovery and development of antibiotics. There is no panacea for the antibacterial resistance crisis; instead, a multifaceted approach is called for. In this Perspective we make the case that, in the face of evolving clinical needs and enabling technologies, numerous validated antibacterial targets and associated lead molecules deserve a second look. At the same time, many worthy targets lack good leads despite harboring druggable active sites. Creative and inspired techniques buoy discovery efforts; while soil screening efforts frequently lead to antibiotic rediscovery, researchers have found success searching for new antibiotic leads by studying underexplored ecological niches or by leveraging the abundance of available data from genome mining efforts. The judicious use of "polypharmacology" (i.e., the ability of a drug to alter the activities of multiple targets) can also provide new opportunities, as can the continued search for inhibitors of resistance enzymes with the capacity to breathe new life into old antibiotics. We conclude by highlighting available pharmacoeconomic models for antibacterial discovery and development while making the case for new ones.
Assuntos
Antibacterianos/química , Descoberta de Drogas , Alquil e Aril Transferases/química , Alquil e Aril Transferases/metabolismo , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/metabolismo , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/metabolismo , beta-Lactamases/química , beta-Lactamases/metabolismoRESUMO
Aztreonam, first discovered in 1980, is an FDA approved, intravenous, monocyclic beta-lactam antibiotic. Aztreonam is active against Gram-negative bacteria and is still used today. The oral bioavailability of aztreonam in humans is less than 1%. Herein we describe the design and synthesis of potential oral prodrugs of aztreonam.
RESUMO
Only one FDA-approved ß-lactamase inhibitor has ever been orally available: clavulanic acid, approved in 1984. Avibactam, approved by FDA in 2015, is the first of a new class of BLIs called diazabicyclooctanes, or "DBOs". This class has much broader coverage than clavulanic acid but can only be administered by intravenous injection. Herein, we describe the synthesis and testing of the first approved BLI to be rendered orally bioavailable since clavulanic acid (1984).
Assuntos
Compostos Azabicíclicos/metabolismo , Compostos Azabicíclicos/farmacologia , Desenho de Fármacos , Pró-Fármacos/metabolismo , Sulfatos/química , Inibidores de beta-Lactamases/metabolismo , Inibidores de beta-Lactamases/farmacologia , Absorção Fisico-Química , Administração Oral , Animais , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/farmacocinética , Disponibilidade Biológica , Cães , Testes de Sensibilidade Microbiana , Ratos , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/farmacocinéticaRESUMO
Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.
Assuntos
Inibidores de Caspase , Caspases/química , Técnicas de Química Combinatória/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Células Jurkat/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Caspase 3 , Caspases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/classificação , Humanos , Células Jurkat/metabolismo , Espectrometria de Massas/métodos , Modelos Moleculares , Biblioteca de PeptídeosRESUMO
A series of novel beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure-activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2' substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.
Assuntos
Endopeptidases/química , Etilaminas/síntese química , Inibidores de Proteases/síntese química , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Dipeptídeos/síntese química , Dipeptídeos/química , Dipeptídeos/farmacologia , Etilaminas/química , Etilaminas/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Isothiazolidinones are a rare but potentially important chemical moiety in biochemistry. We report the identification of several thiol, phosphinate, and carbon nucleophiles that form covalent adducts by addition to the sulfenamide sulfur. This reduction is selective for isothiazolidinones over similar peptide disulfides. We synthesized a coumarin-based thioacid nucleophile which shows a marked fluorescence increase after addition to an isothiazolidinone sulfenamide bond. [structure: see text]
Assuntos
Peptídeos/química , Tiazóis/química , Cumarínicos/química , Corantes Fluorescentes , Espectroscopia de Ressonância Magnética , Organofosfonatos , Oxirredução , Espectrometria de Fluorescência , Espectrofotometria Infravermelho , Compostos de Sulfidrila , Enxofre/químicaRESUMO
The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K(i) values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.
Assuntos
Ácido Aspártico/síntese química , Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Salicilatos/síntese química , Sulfonamidas/síntese química , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Benzoxazóis/síntese química , Benzoxazóis/química , Sítios de Ligação , Caspase 3 , Caspases/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Fluorenos/síntese química , Fluorenos/química , Humanos , Ligação Proteica , Salicilatos/química , Sulfonamidas/química , Tiofenos/síntese química , Tiofenos/químicaRESUMO
Solid-phase synthesis of beta-sultams amenable for construction of sulfonyl beta-lactam analogue combinatorial libraries is reported. Imine intermediates generated from polymer-immobilized amino acids and aldehydes are reacted with (chlorosulfonyl)acetates in the presence of pyridine to afford the solid-phase-tethered beta-sultam products. The latter can be released from support by acidic cleavage (TFA) or photocleavage, depending on the nature of the linker employed (acid-labile or photolabile linkers). Immobilized 4-(9-fluorenyl)methoxycarbonyl beta-sultams are further functionalized on supports to afford, upon cleavage, the respective carboxy and amido thiazetidine derivatives. The method can be employed in production of beta-sultam libraries for identification of new antibacterial agents.
RESUMO
Thiazole peptide GE2270 A (1) possesses potent antimicrobial activity against many gram-positive pathogens, including methicillin resistant Staphylococcus aureus (S. aureus, MRSA; MIC(90)=0.06 microg/mL) and vancomycin resistant Enterococcus spp. (VRE; MIC(90)=0.03 microg/mL); however its poor aqueous solubility has prohibited its development for the clinical treatment of infections. An integrated combinatorial and medicinal chemistry program was employed to identify derivatives of 1 that retain activity but possess greatly enhanced aqueous solubility.
Assuntos
Antibacterianos/síntese química , Produtos Biológicos/síntese química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/síntese química , Peptídeos , Tiazóis/química , Tiazóis/síntese química , Antibacterianos/química , Produtos Biológicos/química , Técnicas de Química Combinatória , Testes de Sensibilidade MicrobianaRESUMO
The design and synthesis of a series of novel, reversible, small molecule inhibitors of caspase-3 are described.